Metal-free direct arylation of dialkyl phosphonates for the synthesis of mixed alkyl aryl phosphonates

ABSTRACT

Provided herein are phosphates, thiophosphates, phosphonates, and phosphinates, methods of making same, and methods of using these compounds and methods for the generation of pharmaceutically relevant phosphate, phosphonate, and phosphinate analogs. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase of International ApplicationNo. PCT/US2018/045224, filed on Aug. 3, 2018, which claims the benefitof U.S. Provisional Application No. 62/540,773, filed on Aug. 3, 2017and U.S. Provisional Application No. 62/610,825, filed on Dec. 27, 2017,which are incorporated herein fully by reference in their entireties.

BACKGROUND

Organophosphonate compounds are ubiquitous structural motifs widelypresent in pharmaceuticals (Horsman and Zechel (2017) Chem. Rev. 117:5704; Mucha et al. (2011) 54: 5955; McGrath et al. (2013) Nat. Rev.Microbiol. 11: 412), agrochemicals (Nowack (2003) Water Res. 37: 2533;Duke and Powles (2008) Pest Manage. Sci. 64: 319), and ligand scaffolds(Martin and Buchwald (2008) Acc. Chem. Res. 41: 1461), highlighting thesignificance of these structures. Among them, mixed alkyl arylphosphonates have attracted significant attention in nucleosidephosphonate prodrugs (Pradere et al. (2014) Chem. Rev. 114: 9154;Thornton et al. (2016) J. Med. Chem. 59: 10400; Okon et al. (2017) J.Med. Chem. 60: 8131) and in coordination chemistry for the study ofbiological system A (FIG. 1; Park et al. (2016) ACS Catal. 6: 7458;Wieczorek et al. (2012) Organometallics 31: 2810; Galbiati et al. (2015)Bioconjugate Chem. 26: 680; Boersma et al. (2008) ChemBioChem 9: 1110).Mixed phosphonates show a wide range of biological activities such asphosphonate prodrugs of butyrophilin ligand B (Foust et al. (2017) ACSMed. Chem. Lett. 8: 914) and antibacterial reagent C (Kazuo et al. JP48018461 B 19730606, 1973). They are also used as γ-glutamyltranspeptidase inhibitors D (Kamiyama et al. (2016) Bioorg. Med. Chem.24: 5340; Nakajima et al. (2014) Bioorg. Med. Chem. 22: 1176) andesterase inhibitors E (Tramontano et al. (2000) Appl. Biochem.Biotechnol. 83: 233). Moreover, due to their unique structuralproperties of a hydrolysable P—O bond, mixed phosphonate units have beenutilized as fluorogenic analogues to study biological mechanisms.

Current synthetic approaches toward mixed alkyl aryl phosphonatespredominantly rely on stepwise processes involving substitution reactionof pre-generated alkyl phosphonochloridates with arenols (FIG. 2A)(Foust et al. (2017) ACS Med. Chem. Lett. 8: 914; Fukuto and Metcalf(1959) J. Am. Chem. Soc. 81: 372; Nowlan et al. (2006) J. Am. Chem. Soc.128: 15892; Bera et al. (2016) ACS Catal. 6: 3575). These methods employphosphonochloridates. In 2014, Feringa and co-workers (Fañanás-Mastraland Feringa (2014) J. Am. Chem. Soc. 136: 9894) disclosed an efficientcopper-catalyzed direct arylation of dialkylphosphonates withdiaryliodonium salts for the synthesis of mixed alkyl aryl phosphonates,which requires elevated reaction temperature and extra steps to preparediaryliodonium salts (FIG. 2B). Therefore, a directaryloxylation/alkyloxylation of dialkylphosphonates in one-pot usingphenols/alcohols under mild reaction conditions is an ideal andstep-economic strategy to generate mixed phosphonates. However, thereare several challenges: (1) as compared to the reactivephosphonochloridates, P(O)—H (Wang et al. (2010) J. Org. Chem. 75: 3890;Atherton and Todd (1947) J. Chem. Soc. 674), and P(O)—OH compounds(Xiong et al. (2015) ACS Catal. 5: 537; Xiong et al. (2015) Tetrahedron71: 9293; Keglevich et al. (2012) Org. Biomol. Chem. 10: 2011), thephosphonate moieties are chemically inert; and (2) for the mixedphosphonate synthesis, the reactivity and chemoselectivity must becarefully controlled to prevent dual substitution of the twin alkoxygroups.

Triflic anhydride (Tf₂O)-mediated activation of carbonyl compounds suchas ketones, aldehydes, and amides as well as sulfoxides has emerged as apowerful synthetic tool in organic synthesis (Kaiser and Maulide (2016)J. Org. Chem. 81: 4421; Baraznenok et al. (2000) Tetrahedron 56: 3077;Chassaing et al. (2012) Tetrahedron 68: 7245; Shang et al. (2017) J. Am.Chem. Soc. 139: 4211; Eberhart and Procter (2013) Angew. Chem. Int. Ed.52: 4008; Angew. Chem. 125: 4100; Kobatake et al. (2010) Angew. Chem.Int. Ed. 49: 2340; Angew. Chem. 122: 2390). Similarly, the activation ofphosphorus compounds with P═O bond, especially phosphine oxides, wasalso achieved by Tf₂O (Hendrickson and Schwartzman (1975) TetrahedronLetters 16: 277; McCauley (2012) Synlett 23: 2999). Recently, Miura andco-workers (Unoh et al. (2017) J. Am. Chem. Soc. 139: 6106) reported anelegant strategy for the activation of H-phosphine oxides. Anelectrophilic phosphorus species (P-species) generated from a diarylphosphine oxide and Tf₂O reacts with an alkyne to form a reactivephosphirenium cation, which undergoes arylative ring-opening reaction toafford phosphinative cyclization product (FIG. 2C). Despite thedemonstration of electrophilic P-species from the secondaryarylphosphine oxides and Tf₂O at elevated temperature (Unoh et al.(2017) J. Am. Chem. Soc. 139: 6106; Yuan et al. (2018) Org. Biomol.Chem. 16: 30), the activation of dialkylphosphonates with Tf₂O at roomtemperature to generate electrophilic P-species remains undeveloped.Consequently, the development of direct functionalization strategies foraccessing aryl phosphonates and mixed phosphonates that have good yieldsand functional group tolerance is highly desirable. These needs andothers are met by the present invention.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tophosphates, thiophosphates, phosphonates, and phosphinates, methods ofmaking same, and methods of using these compounds and methods for thegeneration of pharmaceutically relevant phosphate, phosphonate, andphosphinate analogs.

Disclosed are methods of making a compound having a structurerepresented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein R² isselected from hydrogen, C1-C8 alkyl substituted with 0-1 phenyl groups,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar²,—(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl groups; wherein Ar², when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂(C═S)NR₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³ when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl, or a salt thereof, the methodcomprising the step of reacting a phosphonate derivative having astructure represented by a formula:

wherein R⁴ is C1-C4 alkyl, provided that R² and R⁴ are different, or asalt thereof, with a nucleophile having a structure represented by aformula:

in the presence of an activating agent and a base.

Also disclosed are methods of making a compound having a structurerepresented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein Ar² isselected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar⁴ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl, or a salt thereof, the method comprising the step of reacting aphosphonate derivative having a structure represented by a formula:

wherein R³ is C1-C4 alkyl, or a salt thereof, with a nucleophile havinga structure represented by a formula:

in the presence of an activating agent and a base.

Also disclosed are compounds having a structure represented by aformula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein R² isselected from hydrogen, C1-C8 alkyl substituted with 0-1 phenyl groups,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar²,—(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl groups; wherein Ar², when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³ when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl, or a salt thereof, the methodcomprising the step of reacting a phosphonate derivative having astructure represented by a formula:

wherein R⁴ is C1-C4 alkyl, provided that R² and R⁴ are different, or asalt thereof, with a nucleophile having a structure represented by aformula:

in the presence of an activating agent and a base.

Also disclosed are compounds having a structure represented by aformula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein Ar² isselected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar⁴ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl, or a salt thereof, the method comprising the step of reacting aphosphonate derivative having a structure represented by a formula:

wherein R³ is C1-C4 alkyl, or a salt thereof, with a nucleophile havinga structure represented by a formula:

in the presence of an activating agent and a base.

Also disclosed are methods of using a disclosed compound.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows representative examples of pharmaceutically-relevant mixedalkyl aryl phosphonates.

FIG. 2A-C show representative synthetic routes toward mixedphosphonates. Specifically, an exemplary method for the synthesis ofmixed phosphonates via a substitution reaction (FIG. 2A),copper-catalyzed arylation of phosphonates (FIG. 2B), and Tf₂O-mediatedelectrophilic phosphination/cyclization of alkynes (FIG. 2C) is shown.

FIG. 3 shows Tf₂O-promoted aryloxylation/alkyloxylation of phosphonatesas further disclosed herein.

FIG. 4 shows representative ¹H NMR spectra of the reaction mixtures ofequations (1)-(3).

FIG. 5 shows a representative schematic illustrating the use of acontinuous flow system for phosphate synthesis.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. DEFINITIONS

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate aspects, can also beprovided in combination in a single aspect. Conversely, various featuresof the disclosure which are, for brevity, described in the context of asingle aspect, can also be provided separately or in any suitablesubcombination.

For the terms “for example” and “such as,” and grammatical equivalencesthereof, the phrase “and without limitation” is understood to followunless explicitly stated otherwise.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and salts thereof (e.g., pharmaceutically acceptablesalts), can be found together with other substances such as water andsolvents (e.g., hydrates and solvates).

Compounds provided herein also can include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers that are isomeric protonation stateshaving the same empirical formula and total charge. Example prototropictautomers include ketone-enol pairs, amide-imidic acid pairs,lactam-lactim pairs, enamine-imine pairs, and annular forms where aproton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds provided herein can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include hydrogen, tritium, anddeuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Also provided herein are pharmaceutically acceptable salts of thecompounds described herein. As used herein, the term “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the compounds provided herein include theconventional non-toxic salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. The pharmaceuticallyacceptable salts of the compounds provided herein can be synthesizedfrom the parent compound that contains a basic or acidic moiety byconventional chemical methods. Generally, such salts can be prepared byreacting the free acid or base forms of these compounds with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two. In various aspects, anon-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol,ethanol, iso-propanol, or butanol) or acetonitrile (ACN) can be used.Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977). Conventionalmethods for preparing salt forms are described, for example, in Handbookof Pharmaceutical Salts. Properties, Selection, and Use, Wiley-VCH,2002.

In various aspects, the compounds provided herein, or salts thereof, aresubstantially isolated. By “substantially isolated” is meant that thecompound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

As used herein, chemical structures that contain one or morestereocenters depicted with dashed and bold bonds (i.e.,) are meant toindicate absolute stereochemistry of the stereocenter(s) present in thechemical structure. As used herein, bonds symbolized by a simple line donot indicate a stereo-preference. Unless otherwise indicated to thecontrary, chemical structures, which include one or more stereocenters,illustrated herein without indicating absolute or relativestereochemistry encompass all possible stereoisomeric forms of thecompound (e.g., diastereomers and enantiomers) and mixtures thereof.Structures with a single bold or dashed line, and at least oneadditional simple line, encompass a single enantiomeric series of allpossible diastereomers.

Resolution of racemic mixtures of compounds can be carried out usingappropriate methods. An exemplary method includes fractionalrecrystallization using a chiral resolving acid that is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, orthe various optically active camphorsulfonic acids such ascamphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofmethylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent compositions canbe determined by one skilled in the art.

The expressions “ambient temperature” and “room temperature” as usedherein are understood in the art and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “Cn-Cm” indicates a range thatincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C1-C4, C1-C6, and the like.

As used herein, the term “Cn-Cm alkyl,” employed alone or in combinationwith other terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched, having n to m carbons. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In various aspects, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “Cn-Cm alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In various aspects,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “Cn-Cm alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In various aspects, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “Cn-Cm alkylene,” employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl,butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl, and the like. In various aspects, the alkylenemoiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbonatoms.

As used herein, the term “Cn-Cm alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy),tert-butoxy, and the like. In various aspects, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “Cn-Cm alkylamino” refers to a group of formula—NH(alkyl), wherein the alkyl group has n to m carbon atoms. In variousaspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “Cn-Cm alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “Cn-Cm alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Invarious aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “Cn-Cm alkylcarbonylamino” refers to a group offormula —NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “Cn-Cm alkylsulfonylamino” refers to a group offormula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “Cn-Cm alkylaminosulfonyl” refers to a group offormula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “di(Cn-Cm alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In various aspects, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “Cn-Cm alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or1 to 3 carbon atoms.

As used herein, the term “di(Cn-Cm alkyl)aminosulfonylamino” refers to agroup of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In various aspects, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino,” employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “Cn-Cm alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or1 to 3 carbon atoms.

As used herein, the term “di(Cn-Cm alkyl)aminocarbonylamino” refers to agroup of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In various aspects, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “Cn-Cm alkylcarbamoyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “Cn-Cm alkylthio” refers to a group of formula—S-alkyl, wherein the alkyl group has n to m carbon atoms. In variousaspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “Cn-Cm alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Invarious aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “Cn-Cm alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl,” employed alone or in combinationwith other terms, refers to a —C(═O)— group, which may also be writtenas C(O).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “(Cn-Cm)(Cn-Cm)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In various aspects, each alkyl groupindependently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(Cn-Cm-alkyl)carbamyl” refers to a group offormula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In various aspects, each alkyl groupindependently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, C1, Br, or I. In various aspects,the halo group is F or Cl.

As used herein, “Cn-Cm haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In various aspects, the haloalkoxy group is fluorinated only. Invarious aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “Cn-Cm haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In various aspects, the haloalkylgroup is fluorinated only. In various aspects, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amine base” refers to a mono-substituted aminegroup (i.e., primary amine base), di-substituted amine group (i.e.,secondary amine base), or a tri-substituted amine group (i.e., tertiaryamine base). Example mono-substituted amine bases include methyl amine,ethyl amine, propyl amine, butyl amine, and the like. Exampledi-substituted amine bases include dimethylamine, diethylamine,dipropylamine, dibutylamine, pyrrolidine, piperidine, azepane,morpholine, and the like. In various aspects, the tertiary amine has theformula N(R′)₃, wherein each R′ is independently C₁₋₆ alkyl, 3-10 membercycloalkyl, 4-10 membered heterocycloalkyl, 1-10 membered heteroaryl,and 5-10 membered aryl, wherein the 3-10 member cycloalkyl, 4-10membered heterocycloalkyl, 1-10 membered heteroaryl, and 5-10 memberedaryl are optionally substituted by 1, 2, 3, 4, 5, or 6 C₁₋₆ alkylgroups. Example tertiary amine bases include trimethylamine,triethylamine, tripropylamine, triisopropylamine, tributylamine,tri-tert-butylamine, N,N-dimethylethanamine,N-ethyl-N-methylpropan-2-amine, N-ethyl-N-isopropylpropan-2-amine,morpholine, N-methylmorpholine, and the like. In various aspects, theterm “tertiary amine base” refers to a group of formula N(R)₃, whereineach R is independently a linear or branched C₁₋₆ alkyl group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10ring-forming carbons (C₃₋₁₀). Ring-forming carbon atoms of a cycloalkylgroup can be optionally substituted by oxo or sulfido (e.g., C(O) orC(S)). Cycloalkyl groups also include cycloalkylidenes. Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Invarious aspects, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl, or adamantyl. In various aspects, thecycloalkyl has 6-10 ring-forming carbon atoms. In various aspects,cycloalkyl is cyclohexyl or adamantyl. Also included in the definitionof cycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of cyclopentane, cyclohexane, andthe like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkylgroups can also include spirocycles. Example heterocycloalkyl groupsinclude pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl,tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, andthe like. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido(e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group canbe attached through a ring-forming carbon atom or a ring-formingheteroatom. In various aspects, the heterocycloalkyl group contains 0 to3 double bonds. In various aspects, the heterocycloalkyl group contains0 to 2 double bonds. Also included in the definition of heterocycloalkylare moieties that have one or more aromatic rings fused (i.e., having abond in common with) to the cycloalkyl ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In various aspects, the heterocycloalkyl has 4-10, 4-7 or4-6 ring atoms with 1 or 2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur and having one or more oxidized ringmembers.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In various aspects, arylgroups have from 6 to about 20 carbon atoms, from 6 to about 15 carbonatoms, or from 6 to about 10 carbon atoms. In various aspects, the arylgroup is a substituted or unsubstituted phenyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In various aspects, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In various aspects, any ring-forming Nin a heteroaryl moiety can be an N-oxide. In various aspects, theheteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In variousaspects, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. Invarious aspects, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

At certain places, the definitions or aspects refer to specific rings(e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

As used herein, the term “electron withdrawing group” (EWG), employedalone or in combination with other terms, refers to an atom or group ofatoms substituted onto a π-system (e.g., substituted onto an aryl orheteroaryl ring) that draws electron density away from the r-systemthrough induction (e.g., withdrawing electron density about a σ-bond) orresonance (e.g., withdrawing electron density about a π-bond orπ-system). Example electron withdrawing groups include, but are notlimited to, halo groups (e.g., fluoro, chloro, bromo, iodo), nitriles(e.g., —CN), carbonyl groups (e.g., aldehydes, ketones, carboxylicacids, acid chlorides, esters, and the like), nitro groups (e.g., —NO₂),haloalkyl groups (e.g., —CH₂F, —CHF₂, —CF₃, and the like), alkenylgroups (e.g., vinyl), alkynyl groups (e.g., ethynyl), sulfonyl groups(e.g., S(O)R, S(O)₂R), sulfonate groups (e.g., —SO₃H), and sulfonamidegroups (e.g., S(O)N(R)₂, S(O)₂N(R)₂). In various aspects, the electronwithdrawing group is selected from the group consisting of halo, C2-C6alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, CN, NO₂, C(═O)OR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)SR^(e1), —NR^(c1)S(O)R^(e1),—NR^(c1)S(O)₂R^(e1), S(═O)R^(e1), S(═O)₂R^(e1), S(═O)NR^(c1)R^(d1),S(═O)₂NR^(c1)R^(d1), and P(O)(OR^(a1))₂. In various aspects, theelectron withdrawing group is selected from the group consisting ofC(═O)OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)SR^(e1),S(═O)R^(e1), S(═O)₂R^(e1), S(═O)NR^(c1)R^(d1), and S(═O)₂NR^(c1)R^(d1).In various aspects, the electron withdrawing group is C(═O)OR^(a1). Invarious aspects, the electron withdrawing group is C(═O)OR^(a1), whereinR^(a1) is C₁₋₆ alkyl or (C₆₋₁₀ aryl)-C₁₋₃ alkylene. In various aspects,the electron withdrawing group is an ester.

As used herein, the term “phosphonate derivative” means anorganophosphorous compound in which the phosphorous atom is attached toat least three oxygen atoms. Thus, examples of phosphonate derivativesinclude, but are not limited to, compounds having a structurerepresented by a formula:

As used herein, the term “phosphinate derivative” means anorganophosphorous compound in which the phosphorous atom is attached toat least two oxygen atoms. Thus, examples of phosphinate derivativesinclude, but are not limited to, compounds having a structurerepresented by a formula:

Preparation of the compounds described herein can involve a reaction inthe presence of an acid or a base. Example acids can be inorganic ororganic acids and include, but are not limited to, strong and weakacids. Example acids include, but are not limited to, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonicacid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid,trifluoroacetic acid, and nitric acid. Example weak acids include, butare not limited to, acetic acid, propionic acid, butanoic acid, benzoicacid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid,octanoic acid, nonanoic acid, and decanoic acid. Example bases include,without limitation, lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, potassium carbonate,sodium bicarbonate, and amine bases. Example strong bases include, butare not limited to, hydroxide, alkoxides, metal amides, metal hydrides,metal dialkylamides and arylamines, wherein; alkoxides include lithium,sodium and potassium salts of methyl, ethyl and t-butyl oxides; metalamides include sodium amide, potassium amide and lithium amide; metalhydrides include sodium hydride, potassium hydride and lithium hydride;and metal dialkylamides include lithium, sodium, and potassium salts ofmethyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, trimethylsilyland cyclohexyl substituted amides (e.g., lithiumN-isopropylcyclohexylamide).

The following abbreviations may be used herein: AcOH (acetic acid); aq.(aqueous); atm. (atmosphere(s)); Br₂ (bromine); Bn (benzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DCM(dichloromethane); DMF (N,N-dimethylformamide); Et (ethyl); Et₂O(diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); EWG (electronwithdrawing group); g (gram(s)); h (hour(s)); H₂ (hydrogen gas); HCl(hydrochloric acid/hydrogen choride); HPLC (high performance liquidchromatography); H₂SO₄ (sulfuric acid); Hz (hertz); I₂ (iodine); IPA(isopropyl alcohol); J (coupling constant); KOH (potassium hydroxide);K₃PO₄ (potassium phosphate); LCMS (liquid chromatography-massspectrometry); LiICA (lithium N-isopropylcyclohexylamide); m(multiplet); M (molar); MS (Mass spectrometry); Me (methyl); MeCN(acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s));mL (milliliter(s)); mmol (millimole(s)); N (normal); NaBH₃CN (sodiumcyanoborohydride); NHP (N-heterocyclic phosphine); NHP—Cl(N-heterocyclic phosphine chloride); Na₂CO₃ (sodium carbonate); NaHCO₃(sodium bicarbonate); NaOH (sodium hydroxide); Na₂SO₄ (sodium sulfate);nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); PCl₃(trichlorophosphine); PMP (4-methoxyphenyl); RP-HPLC (reverse phase highperformance liquid chromatography); t (triplet or tertiary); t-Bu(tert-butyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF(tetrahydrofuran); TLC (thin layer chromatography); g (microgram(s)); μL(microliter(s)); M (micromolar); wt % (weight percent).

B. COMPOUNDS

In one aspect, the invention relates to phosphates, thiophosphates,phosphonates, and phosphinates useful in, for example, the synthesis ofpharmaceuticals, agrochemicals, and ligand scaffolds. The use of thedisclosed compounds in the synthesis of other pharmaceutically activecompounds is also envisioned.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein R² isselected from hydrogen, C1-C8 alkyl substituted with 0-1 phenyl groups,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar²,—(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl groups; wherein Ar², when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³ when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl, or a salt thereof, the methodcomprising the step of reacting a phosphonate derivative having astructure represented by a formula:

wherein R⁴ is C1-C4 alkyl, provided that R² and R⁴ are different, or asalt thereof, with a nucleophile having a structure represented by aformula:

in the presence of an activating agent and a base.

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein Ar² isselected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar⁴ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl, or a salt thereof, the method comprising the step of reacting aphosphinate derivative having a structure represented by a formula:

wherein R³ is C1-C4 alkyl, or a salt thereof, with a nucleophile havinga structure represented by a formula:

in the presence of an activating agent and a base.

In a further aspect, the compound has a structure represented by aformula:

wherein n is 0 or 1; wherein A is selected from O, S, and CHR²¹; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from —(C1-C4alkyl)Ar¹ and Ar¹; wherein Ar¹, when present, is selected from aryl andheteroaryl and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl),—OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰,—(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl),—(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b),—NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b), and —N═NR³²; whereinR³⁰, when present, is selected from hydrogen, C1-C8 alkyl, —(C1-C4alkyl)phenyl, phenyl, and a structure represented by a formula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein R² is selected from —(C1-C4 alkyl)Ar² and Ar²; whereinAr², when present, is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein n is 0 or 1; wherein A is selected from O, S, and CHR²¹; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from —(C1-C4 alkyl)Ar¹and Ar¹; wherein Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein Ar³ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³².

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) isindependently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³².

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) isindependently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In one aspect, n is 0 or 1. In a further aspect, n is 0. In a stillfurther aspect, n is 1.

a. A Groups

In one aspect, wherein A is selected from O, S, NR²⁰, and CHR²¹. In afurther aspect, A is selected from O, S, NH, N(CH₃), CH₂, and CH(CH₃).

In a further aspect, A is selected from O, S, and NR²⁰. In a stillfurther aspect, A is selected from O and NR²⁰. In yet a further aspect,A is selected from S and NR²⁰. In an even further aspect, A is selectedfrom O and S.

In a further aspect, A is selected from O, S, and CHR²¹. In a stillfurther aspect, A is selected from O and CHR²¹. In yet a further aspect,A is selected from S and CHR²¹.

In a further aspect, A is O. In a still further aspect, A is S.

In a further aspect, A is selected from NR²⁰ and CHR²¹. In a stillfurther aspect, A is selected from NH, N(CH₃), CH₂, and CH(CH₃). In yeta further aspect, A is selected from NH and CH₂. In an even furtheraspect, A is selected from N(CH₃) and CH(CH₃).

In a further aspect, A is NR²⁰. In a still further aspect, A is CHR²¹.

b. Q Groups

In one aspect, wherein Q is selected from O, S, and NR²². In a furtheraspect, Q is selected from O, S, NH, and N(CH₃).

In a further aspect, Q is selected from O and NR²². In yet a furtheraspect, Q is selected from S and NR²². In an even further aspect, Q isselected from O and S.

In a further aspect, Q is O. In a still further aspect, Q is S.

In a further aspect, Q is NR²².

c. Z Groups

In one aspect, Z is selected from O, S, and NR²³. In a further aspect, Zis selected from O, S, NH, and N(CH₃).

In a further aspect, Z is selected from O and NR²³. In yet a furtheraspect, Z is selected from S and NR²³. In an even further aspect, Z isselected from O and S.

In a further aspect, Z is O. In a still further aspect, Z is S.

In a further aspect, Z is NR²³.

d. R¹ Groups

In one aspect, R¹ is selected from C1-C8 alkyl, C2-C10 alkenyl, C1-C8haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹, —(C2-C4 alkenyl)Ar¹,—(C2-C4 alkynyl)Ar¹, Ar¹, and a structure represented by a formulaselected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group. In a further aspect, R¹ is selected from C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, —(C1-C4alkyl)Ar¹, —(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and astructure represented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group.

In one aspect, each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl.

In a further aspect, R¹ is selected from —(C1-C4 alkyl)Ar¹, —(C2-C4alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structure represented by aformula selected from:

In a further aspect, R¹ is selected from —(C1-C4 alkyl)Ar¹, —(C2-C4alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, and Ar¹. In a still further aspect, R¹is selected from —CH₂Ar¹, —CH₂CH₂Ar¹, —CH(CH₃)Ar¹, —CH═CHAr¹,—CH═CHCH₂Ar¹, —(C2-C3 alkynyl)Ar¹, and Ar¹. In yet a further aspect, R¹is selected from —CH₂Ar¹, —CH═CHAr¹, —(C2 alkynyl)Ar¹, and Ar¹.

In a further aspect, R¹ is selected from —(C1-C4 alkyl)Ar¹ and Ar¹.

In a further aspect, R¹ is Ar¹. In a still further aspect, R¹ is —(C2-C4alkynyl)Ar¹. In yet a further aspect, selected from R¹ is —(C2-C4alkenyl)Ar¹. In an even further aspect, R¹ is —(C1-C4 alkyl)Ar¹.

In a further aspect, R¹ is a structure represented by a formula selectedfrom:

In a further aspect, R¹ is a structure represented by a formula:

In a further aspect, R¹ is a structure represented by a formula:

In a further aspect, R¹ is selected from C1-C8 alkyl, C2-C10 alkenyl,C1-C8 haloalkyl, and C3-C6 cycloalkyl. In a still further aspect, R¹ isselected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C3-C6cycloalkyl. In yet a further aspect, R¹ is selected from methyl, ethyl,n-propyl, isopropyl, ethenyl, propenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. In an even further aspect, R¹ is selected from methyl,ethyl, ethenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CH₂Cl, cyclopropyl, cyclobutyl, and cyclopentyl. In a still furtheraspect, R¹ is selected from methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, cyclopropyl, and cyclobutyl.

In a further aspect, R¹ is selected from C1-C8 alkyl, C2-C10 alkenyl,and C1-C8 haloalkyl. In a still further aspect, R¹ is selected fromC1-C4 alkyl, C2-C4 alkenyl, and C1-C4 haloalkyl. In yet a furtheraspect, R¹ is selected from methyl, ethyl, n-propyl, isopropyl, ethenyl,propenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F,—CH₂Cl, —CHCl₂, —CC₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl, and —CH(CH₃)CH₂Cl. In aneven further aspect, R¹ is selected from methyl, ethyl, ethenyl, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, and —CH₂CH₂Cl. In a stillfurther aspect, R¹ is selected from methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl,—CHCl₂, and —CCl₃.

In a further aspect, R¹ is C3-C6 cycloalkyl substituted with 0 or 1C1-C4 alkyl group. In a still further aspect, R¹ is C3-C6 cycloalkylsubstituted with 1 C1-C4 alkyl group. In yet a further aspect, R¹ isC3-C6 cycloalkyl substituted with 1 methyl group. In an even furtheraspect, R¹ is unsubstituted C3-C6 cycloalkyl.

e. R² Groups

In one aspect, R² is selected from hydrogen, C1-C8 alkyl substitutedwith 0-1 phenyl groups, C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6cycloalkyl, —(C1-C4 alkyl)Ar², —(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar²,Ar², and a structure represented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group. In a further aspect, R² is selected from hydrogen,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, —(C1-C4alkyl)Ar², —(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and astructure represented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group.

In a further aspect, R² is selected from C1-C8 alkyl substituted with0-1 phenyl groups, C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl,—(C1-C4 alkyl)Ar², —(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and astructure represented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group.

In a further aspect, R² is hydrogen.

In a further aspect, R² is selected from —(C1-C4 alkyl)Ar², —(C2-C4alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and a structure represented by aformula selected from:

In a further aspect, R² is selected from —(C1-C4 alkyl)Ar², —(C2-C4alkenyl)Ar², —(C2-C4 alkynyl)Ar², and Ar². In a still further aspect, R²is selected from —CH₂Ar², —CH₂CH₂Ar², —CH(CH₃)Ar², —CH═CHAr²,—CH═CHCH₂Ar², —(C2-C3 alkynyl)Ar², and Ar². In yet a further aspect, R²is selected from —CH₂Ar², —CH═CHAr², —(C2 alkynyl)Ar², and Ar².

In a further aspect, R² is selected from —(C1-C4 alkyl)Ar² and Ar².

In a further aspect, R² is Ar². In a still further aspect, R² is —(C2-C4alkynyl)Ar². In yet a further aspect, selected from R² is —(C2-C4alkenyl)Ar². In an even further aspect, R² is —(C1-C4 alkyl)Ar².

In a further aspect, R² is a structure represented by a formula selectedfrom:

In a further aspect, R² is a structure represented by a formula:

In a further aspect, R² is a structure represented by a formula:

In a further aspect, R² is selected from C1-C8 alkyl, C2-C10 alkenyl,C1-C8 haloalkyl, and C3-C6 cycloalkyl. In a still further aspect, R² isselected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C3-C6cycloalkyl. In yet a further aspect, R² is selected from methyl, ethyl,n-propyl, isopropyl, ethenyl, propenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. In an even further aspect, R² is selected from methyl,ethyl, ethenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CH₂Cl, cyclopropyl, cyclobutyl, and cyclopentyl. In a still furtheraspect, R² is selected from methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, cyclopropyl, and cyclobutyl.

In a further aspect, R² is selected from C1-C8 alkyl, C2-C10 alkenyl,and C1-C8 haloalkyl. In a still further aspect, R² is selected fromC1-C4 alkyl, C2-C4 alkenyl, and C1-C4 haloalkyl. In yet a furtheraspect, R² is selected from methyl, ethyl, n-propyl, isopropyl, ethenyl,propenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl, and —CH(CH₃)CH₂Cl. In aneven further aspect, R² is selected from methyl, ethyl, ethenyl, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, and —CH₂CH₂Cl. In a stillfurther aspect, R² is selected from methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl,—CHCl₂, and —CCl₃.

In a further aspect, R² is C3-C6 cycloalkyl substituted with 0 or 1C1-C4 alkyl group. In a still further aspect, R² is C3-C6 cycloalkylsubstituted with 1 C1-C4 alkyl group. In yet a further aspect, R² isC3-C6 cycloalkyl substituted with 1 methyl group. In an even furtheraspect, R² is unsubstituted C3-C6 cycloalkyl.

In a further aspect, R² is C1-C8 alkyl substituted with 0-1 phenylgroups. In a still further aspect, R² is C1-C8 alkyl substituted with 1phenyl group. In yet a further aspect, R² is C1-C8 alkyl substitutedwith 0 phenyl groups.

f. R³ Groups

In one aspect, R³ is C1-C4 alkyl. In a further aspect, R³ is selectedfrom methyl, ethyl, n-propyl, and isopropyl. In a still further aspect,R³ is selected from n-butyl, isobutyl, sec-butyl, and tert-butyl. In yeta further aspect, R³ is selected from n-propyl and isopropyl. In an evenfurther aspect, R³ is ethyl. In a still further aspect, R³ is methyl.

g. R⁴ Groups

In one aspect, R⁴ is C1-C4 alkyl. In a further aspect, R⁴ is selectedfrom methyl, ethyl, n-propyl, and isopropyl. In a still further aspect,R⁴ is selected from n-butyl, isobutyl, sec-butyl, and tert-butyl. In yeta further aspect, R⁴ is selected from n-propyl and isopropyl. In an evenfurther aspect, R⁴ is ethyl. In a still further aspect, R⁴ is methyl.

h. R²⁰ Groups

In one aspect, R²⁰, when present, is selected from hydrogen and methyl.In a further aspect, R²⁰, when present, is hydrogen. In a still furtheraspect, R²⁰, when present, is methyl.

In one aspect, each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl. In a furtheraspect, each of R¹ and R²⁰, when present, are optionally covalentlybonded together and, together with the intermediate carbon atoms,comprise a 4- to 6-membered heterocycloalkyl. In a still further aspect,each of R¹ and R²⁰, when present, are optionally covalently bondedtogether and, together with the intermediate carbon atoms, comprise a 5-to 6-membered heterocycloalkyl. In yet a further aspect, each of R¹ andR²⁰, when present, are optionally covalently bonded together and,together with the intermediate carbon atoms, comprise a 6-memberedheterocycloalkyl.

i. R²¹ Groups

In one aspect, R²¹, when present, is selected from hydrogen and methyl.In a further aspect, R²¹, when present, is hydrogen. In a still furtheraspect, R²¹, when present, is methyl.

j. R²² Groups

In one aspect, R²², when present, is selected from hydrogen and C1-C8alkyl. In a further aspect, R²², when present, is selected from hydrogenand C1-C4 alkyl. In a still further aspect, R²², when present, ishydrogen.

In a further aspect, R²², when present, is C1-C8 alkyl. In a stillfurther aspect, R²², when present, is C1-C4 alkyl. In yet a furtheraspect, R²², when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R²², when present, is selectedfrom methyl and ethyl. In a still further aspect, R²², when present, isethyl. In yet a further aspect, R²², when present, is methyl.

In a further aspect, R²², when present, is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, andtert-butyl. In a still further aspect, R²², when present, is selectedfrom hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a furtheraspect, R²², when present, is selected from hydrogen, methyl, and ethyl.In an even further aspect, R²², when present, is selected from hydrogenand ethyl. In a still further aspect, R²², when present, is selectedfrom hydrogen and methyl.

k. R²³ Groups

In one aspect, R²³, when present, is selected from hydrogen and methyl.In a further aspect, R²³, when present, is hydrogen. In a still furtheraspect, R²³, when present, is methyl.

l. R³⁰ Groups

In one aspect, R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

In a further aspect, R³⁰, when present, is selected from hydrogen, C1-C4alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

In a further aspect, R³⁰, when present, is a structure represented by aformula:

In a further aspect, R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, and phenyl. In a still further aspect, R³⁰,when present, is selected from hydrogen, C1-C4 alkyl, —(C1-C4alkyl)phenyl, and phenyl. In yet a further aspect, R³⁰ when present, isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,R³⁰, when present, is selected from hydrogen, methyl, ethyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In a still further aspect,R³⁰, when present, is selected from hydrogen, methyl, —(CH₂)phenyl,—(CH(CH₃))phenyl, and phenyl.

In a further aspect, R³⁰, when present, is selected from —(C1-C4alkyl)phenyl and phenyl. In a still further aspect, R³⁰, when present,is selected from —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an evenfurther aspect, R³⁰, when present, is —(CH₂)phenyl. In a still furtheraspect, R³⁰, when present, is —(CH(CH₃))phenyl. In yet a further aspect,R³⁰, when present, is phenyl.

In a further aspect, R³⁰, when present, is selected from hydrogen andC1-C8 alkyl. In a still further aspect, R³⁰, when present, is selectedfrom hydrogen and C1-C4 alkyl. In yet a further aspect, R³⁰, whenpresent, is selected from hydrogen, methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R³⁰, when present, is selectedfrom hydrogen, methyl, and ethyl. In a still further aspect, R³⁰, whenpresent, is selected from hydrogen and ethyl. In yet a further aspect,R³⁰, when present, is selected from hydrogen and methyl.

In a further aspect, R³⁰, when present, is C1-C8 alkyl. In a stillfurther aspect, R³⁰ when present, is C1-C4 alkyl. In yet a furtheraspect, R³⁰, when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R³⁰, when present, is selectedfrom methyl and ethyl. In a still further aspect, R³⁰, when present, isethyl. In yet a further aspect, R³⁰, when present, is methyl.

In a further aspect, R³⁰, when present, is hydrogen.

m. R^(31a) and R^(31b) Groups

In one aspect, each of R^(31a) and R^(31b), when present, isindependently selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl,and phenyl. In a further aspect, each of R^(31a) and R^(31b), whenpresent, is selected from hydrogen, C1-C4 alkyl, —(C1-C4 alkyl)phenyl,and phenyl.

In a further aspect, each of R^(31a) and R^(31b), when present, isselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl.In a still further aspect, each of R^(31a) and R^(31b), when present, isselected from hydrogen, C1-C4 alkyl, —(C1-C4 alkyl)phenyl, and phenyl.In yet a further aspect, each of R^(31a) and R^(31b), when present, isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,each of R^(31a) and R^(31b), when present, is selected from hydrogen,methyl, ethyl, —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In a stillfurther aspect, each of R^(31a) and R^(31b), when present, is selectedfrom hydrogen, methyl, —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl.

In a further aspect, each of R^(31a) and R^(31b), when present, isselected from —(C1-C4 alkyl)phenyl and phenyl. In a still furtheraspect, each of R^(31a) and R^(31b), when present, is selected from—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,each of R^(31a) and R^(31b), when present, is —(CH₂)phenyl. In a stillfurther aspect, each of R^(31a) and R^(31b), when present, is—(CH(CH₃))phenyl. In yet a further aspect, each of R^(31a) and R^(31b),when present, is phenyl.

In a further aspect, each of R^(31a) and R^(31b), when present, isselected from hydrogen and C1-C8 alkyl. In a still further aspect, eachof R^(31a) and R^(31b), when present, is selected from hydrogen andC1-C4 alkyl. In yet a further aspect, each of R^(31a) and R^(31b), whenpresent, is selected from hydrogen, methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, each of R^(31a) and R^(31b), whenpresent, is selected from hydrogen, methyl, and ethyl. In a stillfurther aspect, each of R^(31a) and R^(31b), when present, is selectedfrom hydrogen and ethyl. In yet a further aspect, each of R^(31a) andR^(31b), when present, is selected from hydrogen and methyl.

In a further aspect, each of R^(31a) and R^(31b), when present, is C1-C8alkyl. In a still further aspect, each of R^(31a) and R^(31b), whenpresent, is C1-C4 alkyl. In yet a further aspect, each of R^(31a) andR^(31b), when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, each of R^(31a) and R^(31b), whenpresent, is selected from methyl and ethyl. In a still further aspect,each of R^(31a) and R^(31b), when present, is ethyl. In yet a furtheraspect, each of R^(31a) and R^(31b), when present, is methyl.

In a further aspect, each of R^(31a) and R^(31b), when present, ishydrogen.

n. R³² Groups

In one aspect, R³², when present, is selected from hydrogen, C1-C4alkyl, and phenyl. In a further aspect, R³², when present, is hydrogen.

In a further aspect, R³², when present, is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, and phenyl. In a still furtheraspect, R³², when present, is selected from hydrogen, methyl, ethyl, andphenyl. In yet a further aspect, R³², when present, is selected fromhydrogen, methyl, and phenyl.

In a further aspect, R³², when present, is selected from hydrogen andC1-C4 alkyl. In a still further aspect, R³², when present, is selectedfrom hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a furtheraspect, R³², when present, is selected from hydrogen, methyl, and ethyl.In an even further aspect, R³², when present, is selected from hydrogenand ethyl. In a still further aspect, R³², when present, is selectedfrom hydrogen and methyl.

In a further aspect, R³², when present, is phenyl.

o. R³³ Groups

In one aspect, R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

In a further aspect, R³³, when present, is selected from hydrogen, C1-C4alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

In a further aspect, R³³, when present, is a structure represented by aformula:

In a further aspect, R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, and phenyl. In a still further aspect, R³³,when present, is selected from hydrogen, C1-C4 alkyl, —(C1-C4alkyl)phenyl, and phenyl. In yet a further aspect, R³³ when present, isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,R³³, when present, is selected from hydrogen, methyl, ethyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In a still further aspect,R³³, when present, is selected from hydrogen, methyl, —(CH₂)phenyl,—(CH(CH₃))phenyl, and phenyl.

In a further aspect, R³³, when present, is selected from —(C1-C4alkyl)phenyl and phenyl. In a still further aspect, R³³, when present,is selected from —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an evenfurther aspect, R³³, when present, is —(CH₂)phenyl. In a still furtheraspect, R³³, when present, is —(CH(CH₃))phenyl. In yet a further aspect,R³³, when present, is phenyl.

In a further aspect, R³³, when present, is selected from hydrogen andC1-C8 alkyl. In a still further aspect, R³³, when present, is selectedfrom hydrogen and C1-C4 alkyl. In yet a further aspect, R³³, whenpresent, is selected from hydrogen, methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R³³, when present, is selectedfrom hydrogen, methyl, and ethyl. In a still further aspect, R³³, whenpresent, is selected from hydrogen and ethyl. In yet a further aspect,R³³, when present, is selected from hydrogen and methyl.

In a further aspect, R³³, when present, is C1-C8 alkyl. In a stillfurther aspect, R³³, when present, is C1-C4 alkyl. In yet a furtheraspect, R³³, when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R³³, when present, is selectedfrom methyl and ethyl. In a still further aspect, R³³, when present, isethyl. In yet a further aspect, R³³, when present, is methyl.

In a further aspect, R³³, when present, is hydrogen.

p. R^(34a) and R^(34b) Groups

In one aspect, each of R^(34a) and R^(34b), when present, isindependently selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl,and phenyl. In a further aspect, each of R^(34a) and R^(34b), whenpresent, is selected from hydrogen, C1-C4 alkyl, —(C1-C4 alkyl)phenyl,and phenyl.

In a further aspect, each of R^(34a) and R^(34b), when present, isselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl.In a still further aspect, each of R^(34a) and R^(34b), when present, isselected from hydrogen, C1-C4 alkyl, —(C1-C4 alkyl)phenyl, and phenyl.In yet a further aspect, each of R^(34a) and R^(34b), when present, isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,each of R^(34a) and R^(34b), when present, is selected from hydrogen,methyl, ethyl, —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In a stillfurther aspect, each of R^(34a) and R^(34b), when present, is selectedfrom hydrogen, methyl, —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl.

In a further aspect, each of R^(34a) and R^(34b), when present, isselected from —(C1-C4 alkyl)phenyl and phenyl. In a still furtheraspect, each of R^(34a) and R^(34b), when present, is selected from—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,each of R^(34a) and R^(34b), when present, is —(CH₂)phenyl. In a stillfurther aspect, each of R^(34a) and R^(34b), when present, is—(CH(CH₃))phenyl. In yet a further aspect, each of R^(34a) and R^(34b),when present, is phenyl.

In a further aspect, each of R^(34a) and R^(34b), when present, isselected from hydrogen and C1-C8 alkyl. In a still further aspect, eachof R^(34a) and R^(34b), when present, is selected from hydrogen andC1-C4 alkyl. In yet a further aspect, each of R^(34a) and R^(34b), whenpresent, is selected from hydrogen, methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, each of R^(34a) and R^(34b), whenpresent, is selected from hydrogen, methyl, and ethyl. In a stillfurther aspect, each of R^(34a) and R^(34b), when present, is selectedfrom hydrogen and ethyl. In yet a further aspect, each of R^(34a) andR^(34b), when present, is selected from hydrogen and methyl.

In a further aspect, each of R^(34a) and R^(34b), when present, is C1-C8alkyl. In a still further aspect, each of R^(34a) and R^(34b), whenpresent, is C1-C4 alkyl. In yet a further aspect, each of R^(34a) andR^(34b), when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, each of R^(34a) and R^(34b), whenpresent, is selected from methyl and ethyl. In a still further aspect,each of R^(34a) and R^(34b), when present, is ethyl. In yet a furtheraspect, each of R^(34a) and R^(34b), when present, is methyl.

In a further aspect, each of R^(34a) and R^(34b), when present, ishydrogen.

q. R³⁵ Groups

In one aspect, R³⁵, when present, is selected from hydrogen, C1-C4alkyl, and phenyl. In a further aspect, R³⁵, when present, is hydrogen.

In a further aspect, R³⁵, when present, is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, and phenyl. In a still furtheraspect, R³⁵, when present, is selected from hydrogen, methyl, ethyl, andphenyl. In yet a further aspect, R³⁵, when present, is selected fromhydrogen, methyl, and phenyl.

In a further aspect, R³⁵, when present, is selected from hydrogen andC1-C4 alkyl. In a still further aspect, R³⁵, when present, is selectedfrom hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a furtheraspect, R³⁵, when present, is selected from hydrogen, methyl, and ethyl.In an even further aspect, R³⁵, when present, is selected from hydrogenand ethyl. In a still further aspect, R³⁵, when present, is selectedfrom hydrogen and methyl.

In a further aspect, R³⁵, when present, is phenyl.

r. R³⁶ Groups

In one aspect, R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

In a further aspect, R³⁶, when present, is selected from hydrogen, C1-C4alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

In a further aspect, R³⁶, when present, is a structure represented by aformula:

In a further aspect, R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, and phenyl. In a still further aspect, R³⁶,when present, is selected from hydrogen, C1-C4 alkyl, —(C1-C4alkyl)phenyl, and phenyl. In yet a further aspect, R³⁶ when present, isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,R³⁶, when present, is selected from hydrogen, methyl, ethyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In a still further aspect,R³⁶, when present, is selected from hydrogen, methyl, —(CH₂)phenyl,—(CH(CH₃))phenyl, and phenyl.

In a further aspect, R³⁶, when present, is selected from —(C1-C4alkyl)phenyl and phenyl. In a still further aspect, R³⁶, when present,is selected from —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an evenfurther aspect, R³⁶, when present, is —(CH₂)phenyl. In a still furtheraspect, R³⁶, when present, is —(CH(CH₃))phenyl. In yet a further aspect,R³⁶, when present, is phenyl.

In a further aspect, R³⁶, when present, is selected from hydrogen andC1-C8 alkyl. In a still further aspect, R³⁶, when present, is selectedfrom hydrogen and C1-C4 alkyl. In yet a further aspect, R³⁶, whenpresent, is selected from hydrogen, methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R³⁶, when present, is selectedfrom hydrogen, methyl, and ethyl. In a still further aspect, R³⁶, whenpresent, is selected from hydrogen and ethyl. In yet a further aspect,R³⁶, when present, is selected from hydrogen and methyl.

In a further aspect, R³⁶, when present, is C1-C8 alkyl. In a stillfurther aspect, R³⁶ when present, is C1-C4 alkyl. In yet a furtheraspect, R³⁶, when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, R³⁶, when present, is selectedfrom methyl and ethyl. In a still further aspect, R³⁶, when present, isethyl. In yet a further aspect, R³⁶, when present, is methyl.

In a further aspect, R³⁶, when present, is hydrogen.

s. R^(37a) and R^(37b) Groups

In one aspect, each of R^(37a) and R^(37b), when present, isindependently selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl,and phenyl. In a further aspect, each of R^(37a) and R^(37b), whenpresent, is selected from hydrogen, C1-C4 alkyl, —(C1-C4 alkyl)phenyl,and phenyl.

In a further aspect, each of R^(37a) and R^(37b), when present, isselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl.In a still further aspect, each of R^(37a) and R^(37b), when present, isselected from hydrogen, C1-C4 alkyl, —(C1-C4 alkyl)phenyl, and phenyl.In yet a further aspect, each of R^(37a) and R^(37b), when present, isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl,—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,each of R^(37a) and R^(37b), when present, is selected from hydrogen,methyl, ethyl, —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In a stillfurther aspect, each of R^(37a) and R^(37b), when present, is selectedfrom hydrogen, methyl, —(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl.

In a further aspect, each of R^(37a) and R^(37b), when present, isselected from —(C1-C4 alkyl)phenyl and phenyl. In a still furtheraspect, each of R^(37a) and R^(37b), when present, is selected from—(CH₂)phenyl, —(CH(CH₃))phenyl, and phenyl. In an even further aspect,each of R^(37a) and R^(37b), when present, is —(CH₂)phenyl. In a stillfurther aspect, each of R^(37a) and R^(37b), when present, is—(CH(CH₃))phenyl. In yet a further aspect, each of R^(37a) and R^(37b),when present, is phenyl.

In a further aspect, each of R^(37a) and R^(37b), when present, isselected from hydrogen and C1-C8 alkyl. In a still further aspect, eachof R^(37a) and R^(37b), when present, is selected from hydrogen andC1-C4 alkyl. In yet a further aspect, each of R^(37a) and R^(37b), whenpresent, is selected from hydrogen, methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, each of R^(37a) and R^(37b), whenpresent, is selected from hydrogen, methyl, and ethyl. In a stillfurther aspect, each of R^(37a) and R^(37b), when present, is selectedfrom hydrogen and ethyl. In yet a further aspect, each of R^(37a) andR^(37b), when present, is selected from hydrogen and methyl.

In a further aspect, each of R^(37a) and R^(37b), when present, is C1-C8alkyl. In a still further aspect, each of R^(37a) and R^(37b), whenpresent, is C1-C4 alkyl. In yet a further aspect, each of R^(37a) andR^(37b), when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In an even further aspect, each of R^(37a) and R^(37b), whenpresent, is selected from methyl and ethyl. In a still further aspect,each of R^(37a) and R^(37b), when present, is ethyl. In yet a furtheraspect, each of R^(37a) and R^(37b), when present, is methyl.

In a further aspect, each of R^(37a) and R^(37b), when present, ishydrogen.

t. R³⁸ Groups

In one aspect, R³⁸, when present, is selected from hydrogen, C1-C4alkyl, and phenyl. In a further aspect, R³⁸, when present, is hydrogen.

In a further aspect, R³⁸, when present, is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, and phenyl. In a still furtheraspect, R³⁸, when present, is selected from hydrogen, methyl, ethyl, andphenyl. In yet a further aspect, R³⁸, when present, is selected fromhydrogen, methyl, and phenyl.

In a further aspect, R³⁸, when present, is selected from hydrogen andC1-C4 alkyl. In a still further aspect, R³⁸, when present, is selectedfrom hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a furtheraspect, R³⁸, when present, is selected from hydrogen, methyl, and ethyl.In an even further aspect, R³⁸, when present, is selected from hydrogenand ethyl. In a still further aspect, R³⁸, when present, is selectedfrom hydrogen and methyl.

In a further aspect, R³⁸, when present, is phenyl.

u. R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) Groups

In one aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e)is independently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b)SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b),—NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b), and —N═NR³².

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, —O(C2-C4 alkenyl),—OCO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, and —N═NR³².

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, —F, —Cl, —NO₂, —CN,—OH, —SH, —NH₂, methyl, ethyl, propyl, ethenyl, propenyl, ethynyl,propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCH₂F, —OCHF₂, —OCF₃,—OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —CH₂NH₂,—CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —NH(CH₂CH₃)₂, cyclopropyl,cyclobutyl, cyclopentyl, phenyl, —(C═O)CH₃, —(C═O)CH₂CH₃, —(S═O)CH₃,—(S═O)CH₂CH₃, —SO₂CH₃, —SO₂CH₂CH₃, —CO₂CH₃, —CO₂CH₂CH₃, —(C═O)NH₂,—(C═O)NHCH₃, —(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, —O(C═O)NH₂,—O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃, —NHSO₂N(CH₃)₂,—NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂. In a still furtheraspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, ethenyl, ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, —OCH₃, —SCH₃,—CH₂OCH₃, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, cyclopropyl, cyclobutyl, phenyl,—(C═O)CH₃, —(S═O)CH₃, —SO₂CH₃, —CO₂CH₃, —(C═O)NH₂, —(C═O)NHCH₃,—(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, —O(C═O)NH₂,—O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃, —NHSO₂N(CH₃)₂,—NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂. In yet a furtheraspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH,—OCH₂F, —OCHF₂, —OCF₃, —OCH₃, —SCH₃, —CH₂OCH₃, —CH₂NH₂, —NHCH₃,—N(CH₃)₂, cyclopropyl, phenyl, —(C═O)CH₃, —(S═O)CH₃, —SO₂CH₃, —CO₂CH₃,—(C═O)NH₂, —(C═O)NHCH₃, —(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—O(C═O)NH₂, —O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃,—NHSO₂N(CH₃)₂, —NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen and C6-C10 aryl. In astill further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen and phenyl.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, propyl,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃,—OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, and —NH(CH₂CH₃)₂. In a still further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, —CH₂F,—CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —OCH₃, —SCH₃, —CH₂OCH₃, —NHCH₃, and—N(CH₃)₂. In yet a further aspect, each of R^(40a), R^(40b), R^(40c),R^(40d) and R^(40e) is independently selected from hydrogen, —F, —Cl,—NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, —OCH₃, —SCH₃, —CH₂OCH₃, —NHCH₃, and —N(CH₃)₂.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In afurther aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e)is independently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, propyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, and —OCH₂CH₃. In a still furtheraspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, and—OCH₃. In yet a further aspect, each of R^(40a), R^(40b), R^(40c),R^(40d), and R^(40e) is independently selected from hydrogen, —F, —Cl,—NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, and —OCH₃.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, C1-C4 alkyl, C1-C4haloalkyl, and C1-C4 alkoxy. In a further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen, methyl, ethyl, propyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, and —OCH₂CH₃. In a still furtheraspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, methyl, ethyl, —CH₂F, —CHF₂, —CF₃,—CH₂Cl, —CHCl₂, —CCl₃, and —OCH₃. In yet a further aspect, each ofR^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) is independentlyselected from hydrogen, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, and —OCH₃.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, C1-C4 alkyl, and C1-C4alkoxy. In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d),and R^(40e) is independently selected from hydrogen, methyl, ethyl,propyl, —OCH₃, and —OCH₂CH₃. In a still further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen, methyl, ethyl, and —OCH₃. In yet a further aspect, each ofR^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) is independentlyselected from hydrogen, methyl, and —OCH₃.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen and C1-C4 haloalkyl. Ina further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, and —CH₂CH₂Cl. In a still furtheraspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) isindependently selected from hydrogen, —CH₂F, —CHF₂, —CF₃, —CH₂Cl,—CHCl₂, and —CCl₃. In yet a further aspect, each of R^(40a), R^(40b),R^(40c), R^(40d), and R^(40e) is independently selected from hydrogen,—CHF₂, —CF₃, —CHCl₂, and —CCl₃. In an even further aspect, each ofR^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) is independentlyselected from hydrogen, —CF₃, and —CCl₃. In a still further aspect, eachof R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) is independentlyselected from hydrogen and —CF₃. In yet a further aspect, each ofR^(40a), R^(40b), R^(40c), R^(40d), and R^(40e) is independentlyselected from hydrogen and —CCl₃.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, and —OCH(CH₃)₂. In a still further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen, —OCH₃, and —OCH₂CH₃. In yet a further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen and —OCH₂CH₂CH₃. In an even further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen and —OCH(CH₃)₂. In a still further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen and —OCH₂CH₃. In yet a further aspect, each of R^(40a),R^(40b), R^(40c), R^(40d), and R^(40e) is independently selected fromhydrogen and —OCH₃.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a stillfurther aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), and R^(40e)is independently selected from hydrogen, methyl, ethyl, n-propyl, andi-propyl. In yet a further aspect, each of R^(40a), R^(40b), R^(40c),R^(40d), and R^(40e) is independently selected from hydrogen, methyl,and ethyl. In an even further aspect, each of R^(40a), R^(40b), R^(40c),R^(40d), and R^(40e) is independently selected from hydrogen and ethyl.In a still further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d),and R^(40e) is independently selected from hydrogen and methyl.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, C1-C4 haloalkyl, C1-C4alkoxy, and C6-C10 aryl.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is independently selected from hydrogen, —CF₃, —OCH₃, andphenyl.

In a further aspect, each of R^(40a), R^(40b), R^(40c), R^(40d), andR^(40e) is hydrogen.

v. R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) Groups

In one aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e)is independently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, —O(C2-C4 alkenyl),—OCO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, and —N═NR³².

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, —F, —Cl, —NO₂, —CN,—OH, —SH, —NH₂, methyl, ethyl, propyl, ethenyl, propenyl, ethynyl,propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCH₂F, —OCHF₂, —OCF₃,—OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —CH₂NH₂,—CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —NH(CH₂CH₃)₂, cyclopropyl,cyclobutyl, cyclopentyl, phenyl, —(C═O)CH₃, —(C═O)CH₂CH₃, —(S═O)CH₃,—(S═O)CH₂CH₃, —SO₂CH₃, —SO₂CH₂CH₃, —CO₂CH₃, —CO₂CH₂CH₃, —(C═O)NH₂,—(C═O)NHCH₃, —(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, —O(C═O)NH₂,—O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃, —NHSO₂N(CH₃)₂,—NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂. In a still furtheraspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) isindependently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, ethenyl, ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, —OCH₃, —SCH₃,—CH₂OCH₃, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, cyclopropyl, cyclobutyl, phenyl,—(C═O)CH₃, —(S═O)CH₃, —SO₂CH₃, —CO₂CH₃, —(C═O)NH₂, —(C═O)NHCH₃,—(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, —O(C═O)NH₂,—O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃, —NHSO₂N(CH₃)₂,—NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂. In yet a furtheraspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) isindependently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH,—OCH₂F, —OCHF₂, —OCF₃, —OCH₃, —SCH₃, —CH₂OCH₃, —CH₂NH₂, —NHCH₃,—N(CH₃)₂, cyclopropyl, phenyl, —(C═O)CH₃, —(S═O)CH₃, —SO₂CH₃, —CO₂CH₃,—(C═O)NH₂, —(C═O)NHCH₃, —(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—O(C═O)NH₂, —O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃,—NHSO₂N(CH₃)₂, —NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen and C6-C10 aryl. In astill further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen and phenyl.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, propyl,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃,—OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, and —NH(CH₂CH₃)₂. In a still further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, —CH₂F,—CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —OCH₃, —SCH₃, —CH₂OCH₃, —NHCH₃, and—N(CH₃)₂. In yet a further aspect, each of R^(41a), R^(41b), R^(41c),R^(41d) and R^(41e) is independently selected from hydrogen, —F, —Cl,—NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, —OCH₃, —SCH₃, —CH₂OCH₃, —NHCH₃, and —N(CH₃)₂.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In afurther aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e)is independently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, propyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, and —OCH₂CH₃. In a still furtheraspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) isindependently selected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, and—OCH₃. In yet a further aspect, each of R^(41a), R^(41b), R^(41c),R^(41d), and R^(41e) is independently selected from hydrogen, —F, —Cl,—NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, and —OCH₃.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, C1-C4 alkyl, C1-C4haloalkyl, and C1-C4 alkoxy. In a further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen, methyl, ethyl, propyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, and —OCH₂CH₃. In a still furtheraspect, each of R^(41a), R^(41b), R^(41c), R^(41d) and R^(41e) isindependently selected from hydrogen, methyl, ethyl, —CH₂F, —CHF₂, —CF₃,—CH₂Cl, —CHCl₂, —CCl₃, and —OCH₃. In yet a further aspect, each ofR^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) is independentlyselected from hydrogen, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂,—CCl₃, and —OCH₃.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, C1-C4 alkyl, and C1-C4alkoxy. In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d),and R^(41e) is independently selected from hydrogen, methyl, ethyl,propyl, —OCH₃, and —OCH₂CH₃. In a still further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen, methyl, ethyl, and —OCH₃. In yet a further aspect, each ofR^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) is independentlyselected from hydrogen, methyl, and —OCH₃.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen and C1-C4 haloalkyl. Ina further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, and —CH₂CH₂Cl. In a still furtheraspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) isindependently selected from hydrogen, —CH₂F, —CHF₂, —CF₃, —CH₂Cl,—CHCl₂, and —CCl₃. In yet a further aspect, each of R^(41a), R^(41b),R^(41c), R^(41d), and R^(41e) is independently selected from hydrogen,—CHF₂, —CF₃, —CHCl₂, and —CCl₃. In an even further aspect, each ofR^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) is independentlyselected from hydrogen, —CF₃, and —CCl₃. In a still further aspect, eachof R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) is independentlyselected from hydrogen and —CF₃. In yet a further aspect, each ofR^(41a), R^(41b), R^(41c), R^(41d), and R^(41e) is independentlyselected from hydrogen and —CCl₃.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, and —OCH(CH₃)₂. In a still further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen, —OCH₃, and —OCH₂CH₃. In yet a further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen and —OCH₂CH₂CH₃. In an even further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen and —OCH(CH₃)₂. In a still further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen and —OCH₂CH₃. In yet a further aspect, each of R^(41a),R^(41b), R^(41c), R^(41d), and R^(41e) is independently selected fromhydrogen and —OCH₃.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a stillfurther aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), and R^(41e)is independently selected from hydrogen, methyl, ethyl, n-propyl, andi-propyl. In yet a further aspect, each of R^(41a), R^(41b), R^(41c),R^(41d), and R^(41e) is independently selected from hydrogen, methyl,and ethyl. In an even further aspect, each of R^(41a), R^(41b), R^(41c),R^(41d), and R^(41e) is independently selected from hydrogen and ethyl.In a still further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d),and R^(41e) is independently selected from hydrogen and methyl.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, C1-C4 haloalkyl, C1-C4alkoxy, and C6-C10 aryl.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is independently selected from hydrogen, —CF₃, —OCH₃, andphenyl.

In a further aspect, each of R^(41a), R^(41b), R^(41c), R^(41d), andR^(41e) is hydrogen.

w. Ar¹ Groups

In one aspect, Ar¹, when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a further aspect, Ar¹, when present, is selected fromaryl and heteroaryl and is substituted with 0, 1, or 2 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b) SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is selectedfrom aryl and heteroaryl and is substituted with 0 or 1 group selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl),—OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰,—(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl),—(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b),—NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b), and —N═NR³². In yet afurther aspect, Ar¹, when present, is selected from aryl and heteroaryland is monosubstituted with a group selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is selectedfrom aryl and heteroaryl and is unsubstituted.

In a further aspect, Ar¹, when present, is aryl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b)SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b),—NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b), and —N═NR³². In a stillfurther aspect, Ar¹, when present, is aryl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b) SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, is arylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is arylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted aryl.

In a further aspect, Ar¹, when present, is phenyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10phenyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is phenylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 phenyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, is phenylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10phenyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is phenylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10phenyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted phenyl.

In a further aspect, Ar¹, when present, is naphthyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is naphthylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In yet a further aspect, Ar¹, whenpresent, is naphthyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In an even further aspect, Ar¹,when present, is naphthyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In a still further aspect, Ar¹,when present, is unsubstituted naphthyl.

In a further aspect, Ar¹, when present, is 1-naphthyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C101-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is 1-naphthylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 1-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In yet a further aspect, Ar¹, whenpresent, is 1-naphthyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 1-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In an even further aspect, Ar¹,when present, is 1-naphthyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 1-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In a still further aspect, Ar¹,when present, is unsubstituted 1-naphthyl.

In a further aspect, Ar¹, when present, is 2-naphthyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C102-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is 2-naphthylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 2-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In yet a further aspect, Ar¹, whenpresent, is 2-naphthyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 2-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In an even further aspect, Ar¹,when present, is 2-naphthyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 2-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰,—(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In a still further aspect, Ar¹,when present, is unsubstituted 2-naphthyl.

In a further aspect, Ar¹, when present, is benzo[d][1,3]dioxolylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁰,—CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In a still further aspect, Ar¹,when present, is benzo[d][1,3]dioxolyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b) SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, isbenzo[d][1,3]dioxolyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁰,—CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b),—SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b),—NH(C═O)NR^(31a)R^(31b), and —N═NR³². In an even further aspect, Ar¹,when present, is benzo[d][1,3]dioxolyl monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted benzo[d][1,3]dioxolyl.

In a further aspect, Ar¹, when present, is heteroaryl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is heteroarylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, is heteroarylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is heteroarylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted heteroaryl.

In a further aspect, Ar¹, when present, is pyridinyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is pyridinylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, is pyridinylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is pyridinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted pyridinyl.

In a further aspect, Ar¹, when present, is quinolinyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰,—(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is quinolinylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, is quinolinylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is quinolinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted quinolinyl.

In a further aspect, Ar¹, when present, is furanyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, is furanylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In yet a further aspect, Ar¹, when present, is furanylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In an even further aspect, Ar¹, when present, is furanylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³². In a still further aspect, Ar¹, when present, isunsubstituted furanyl.

In a further aspect, Ar¹ is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from C1-C4 haloalkyl, C1-C4 alkoxy, and C6-C10aryl. In a still further aspect, Ar¹ is aryl substituted with 0, 1, or 2groups independently selected from C1-C4 haloalkyl, C1-C4 alkoxy, andC6-C10 aryl. In yet a further aspect, Ar¹ is aryl substituted with 0 or1 group selected from C1-C4 haloalkyl, C1-C4 alkoxy, and C6-C10 aryl. Inan even further aspect, Ar¹ is aryl monosubstituted with a groupselected from C1-C4 haloalkyl, C1-C4 alkoxy, and C6-C10 aryl.

In a further aspect, Ar¹ is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from —CF₃, —OCH₃, and phenyl. In a still furtheraspect, Ar¹ is aryl substituted with 0, 1, or 2 groups independentlyselected from —CF₃, —OCH₃, and phenyl. In yet a further aspect, Ar¹ isaryl substituted with 0 or 1 group selected from —CF₃, —OCH₃, andphenyl. In an even further aspect, Ar¹ is aryl monosubstituted with agroup selected from —CF₃, —OCH₃, and phenyl.

x. Ar² Groups

In one aspect, Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a further aspect, Ar², when present, is selected fromaryl and heteroaryl and is substituted with 0, 1, or 2 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is selectedfrom aryl and heteroaryl and is substituted with 0 or 1 group selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl),—OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³,—(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl),—(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b),—NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In yet afurther aspect, Ar², when present, is selected from aryl and heteroaryland is monosubstituted with a group selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is selectedfrom aryl and heteroaryl and is unsubstituted.

In a further aspect, Ar², when present, is aryl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is arylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl-OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In yet a further aspect, Ar², when present, is arylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is arylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted aryl.

In a further aspect, Ar², when present, is phenyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10phenyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is phenylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 phenyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b34), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In yet a further aspect, Ar², whenpresent, is phenyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 phenyl, —O(C2-C4 alkenyl), —OC₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is phenylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10phenyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted phenyl.

In a further aspect, Ar², when present, is naphthyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is naphthylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b34), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In yet a further aspect, Ar², whenpresent, is naphthyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In an even further aspect, Ar²,when present, is naphthyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In a still further aspect, Ar²,when present, is unsubstituted naphthyl.

In a further aspect, Ar², when present, is 1-naphthyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C101-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is 1-naphthylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 1-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b34), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In yet a further aspect, Ar², whenpresent, is 1-naphthyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 1-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In an even further aspect, Ar²,when present, is 1-naphthyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 1-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In a still further aspect, Ar²,when present, is unsubstituted 1-naphthyl.

In a further aspect, Ar², when present, is 2-naphthyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C102-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is 2-naphthylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 2-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b34), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In yet a further aspect, Ar², whenpresent, is 2-naphthyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 2-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In an even further aspect, Ar²,when present, is 2-naphthyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 2-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³,—(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl),—(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In a still further aspect, Ar²,when present, is unsubstituted 2-naphthyl.

In a further aspect, Ar², when present, is benzo[d][1,3]dioxolylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³³,—CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In a still further aspect, Ar²,when present, is benzo[d][1,3]dioxolyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In yet a further aspect, Ar², when present, isbenzo[d][1,3]dioxolyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³³,—CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b),—SO₂NR^(34a)R^(34b), —O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b),—NH(C═O)NR^(34a)R^(34b), and —N═NR³⁵. In an even further aspect, Ar²,when present, is benzo[d][1,3]dioxolyl monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted benzo[d][1,3]dioxolyl.

In a further aspect, Ar², when present, is heteroaryl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is heteroarylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In yet a further aspect, Ar², when present, is heteroarylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is heteroarylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted heteroaryl.

In a further aspect, Ar², when present, is pyridinyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is pyridinylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In yet a further aspect, Ar², when present, is pyridinylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is pyridinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted pyridinyl.

In a further aspect, Ar², when present, is quinolinyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³,—(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is quinolinylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In yet a further aspect, Ar², when present, is quinolinylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is quinolinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted quinolinyl.

In a further aspect, Ar², when present, is furanyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, is furanylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In yet a further aspect, Ar², when present, is furanylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In an even further aspect, Ar², when present, is furanylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵. In a still further aspect, Ar², when present, isunsubstituted furanyl.

In a further aspect, Ar² is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from C1-C4 haloalkyl, C1-C4 alkoxy, and C6-C10aryl. In a still further aspect, Ar² is aryl substituted with 0, 1, or 2groups independently selected from C1-C4 haloalkyl, C1-C4 alkoxy, andC6-C10 aryl. In yet a further aspect, Ar² is aryl substituted with 0 or1 group selected from C1-C4 haloalkyl, C1-C4 alkoxy, and C6-C10 aryl. Inan even further aspect, Ar² is aryl monosubstituted with a groupselected from C1-C4 haloalkyl, C1-C4 alkoxy, and C6-C10 aryl.

In a further aspect, Ar² is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from —CF₃, —OCH₃, and phenyl. In a still furtheraspect, Ar² is aryl substituted with 0, 1, or 2 groups independentlyselected from —CF₃, —OCH₃, and phenyl. In yet a further aspect, Ar² isaryl substituted with 0 or 1 group selected from —CF₃, —OCH₃, andphenyl. In an even further aspect, Ar² is aryl monosubstituted with agroup selected from —CF₃, —OCH₃, and phenyl.

In a further aspect, Ar² is C6-aryl substituted with 0, 1, 2, or 3groups independently selected from C1-C4 haloalkyl, C1-C4 alkoxy, andC6-C10 aryl. In a still further aspect, Ar² is C6-aryl substituted with0, 1, or 2 groups independently selected from C1-C4 haloalkyl, C1-C4alkoxy, and C6-C10 aryl. In yet a further aspect, Ar² is C6-arylsubstituted with 0 or 1 group selected from C1-C4 haloalkyl, C1-C4alkoxy, and C6-C10 aryl. In an even further aspect, Ar² is C6-arylmonosubstituted with a group selected from C1-C4 haloalkyl, C1-C4alkoxy, and C6-C10 aryl.

In a further aspect, Ar² is C6-aryl substituted with 0, 1, 2, or 3groups independently selected from —CF₃, —OCH₃, and phenyl. In a stillfurther aspect, Ar² is C6-aryl substituted with 0, 1, or 2 groupsindependently selected from —CF₃, —OCH₃, and phenyl. In yet a furtheraspect, Ar² is C6-aryl substituted with 0 or 1 group selected from —CF₃,—OCH₃, and phenyl. In an even further aspect, Ar² is C6-arylmonosubstituted with a group selected from —CF₃, —OCH₃, and phenyl.

In a further aspect, Ar² is C6-aryl substituted with 0, 1, 2, or 3groups independently selected from —CF₃, and phenyl. In a still furtheraspect, Ar² is C6-aryl substituted with 0, 1, or 2 groups independentlyselected from —CF₃, and phenyl. In yet a further aspect, Ar² is C6-arylsubstituted with 0 or 1 group selected from —CF₃, and phenyl. In an evenfurther aspect, Ar² is C6-aryl monosubstituted with a group selectedfrom —CF₃, and phenyl.

y. Ar³ Groups

In one aspect, Ar³ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a further aspect, Ar³ is selected from aryl andheteroaryl and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl),—OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶,—(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl),—(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b), —O(C═O)NR^(37a)R^(37b),—NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b), and —N═NR³⁸. In a stillfurther aspect, Ar³ is selected from aryl and heteroaryl and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is selected from aryl andheteroaryl and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is selected from aryl andheteroaryl and is unsubstituted.

In a further aspect, Ar³ is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is aryl substituted with 0,1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl, —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is aryl substituted with 0 or1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OC₂R³⁶,—CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b),—SO₂NR^(37a)R^(37b), —O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b),—NH(C═O)NR^(37a)R^(37b), and —N═NR³⁸. In an even further aspect, Ar³ isaryl monosubstituted with a group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted aryl.

In a further aspect, Ar³ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 phenyl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is phenyl substituted with0, 1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10phenyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is phenyl substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 phenyl, —O(C2-C4alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is phenyl monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 phenyl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted phenyl.

In a further aspect, Ar³ is naphthyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is naphthyl substituted with0, 1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10naphthyl, —O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is naphthyl substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 naphthyl, —O(C2-C4alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is naphthyl monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 naphthyl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted naphthyl.

In a further aspect, Ar³ is 1-naphthyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C101-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is 1-naphthyl substitutedwith 0, 1, or 2 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C101-naphthyl, —O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is 1-naphthyl substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 1-naphthyl,—O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is 1-naphthylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1—C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C101-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted 1-naphthyl.

In a further aspect, Ar³ is 2-naphthyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C102-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is 2-naphthyl substitutedwith 0, 1, or 2 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C102-naphthyl, —O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is 2-naphthyl substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 2-naphthyl,—O(C2-C4 alkenyl), —OCO₂R³⁶, CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is 2-naphthylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1—C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C102-naphthyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted 2-naphthyl.

In a further aspect, Ar³ is benzo[d][1,3]dioxolyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is benzo[d][1,3]dioxolylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁶,—CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b),—SO₂NR^(37a)R^(37b), —O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b),—NH(C═O)NR^(37a)R^(37b), and —N═NR³⁸. In yet a further aspect, Ar³ isbenzo[d][1,3]dioxolyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁶,—CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b),—SO₂NR^(37a)R^(37b), —O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b),—NH(C═O)NR^(37a)R^(37b), and —N═NR³⁸. In an even further aspect, Ar³ isbenzo[d][1,3]dioxolyl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 benzo[d][1,3]dioxolyl, —O(C2-C4 alkenyl), —OCO₂R³⁶,—CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b),—SO₂NR^(37a)R^(37b), —O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b),—NH(C═O)NR^(37a)R^(37b), and —N═NR³⁸. In a still further aspect, Ar³ isunsubstituted benzo[d][1,3]dioxolyl.

In a further aspect, Ar³ is heteroaryl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is heteroaryl substitutedwith 0, 1, or 2 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is heteroaryl substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is heteroarylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted heteroaryl.

In a further aspect, Ar³ is pyridinyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is pyridinyl substitutedwith 0, 1, or 2 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is pyridinyl substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is pyridinyl monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted pyridinyl.

In a further aspect, Ar³ is quinolinyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is quinolinyl substitutedwith 0, 1, or 2 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶,—(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl),—SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is quinolinyl substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is quinolinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted quinolinyl.

In a further aspect, Ar³ is furanyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is furanyl substituted with0, 1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In yet a further aspect, Ar³ is furanyl substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In an even further aspect, Ar³ is furanyl monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4 alkyl)CO₂R³⁶, —(C2-C4alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸. In a still further aspect, Ar³ is unsubstituted furanyl.

2. Compound Examples

In one aspect, a compound is selected from:

or a salt thereof.

In one aspect, the compound is selected from:

or a salt thereof.

In one aspect, the compound is selected from:

or a salt thereof.

In one aspect, the compound is selected from:

or a salt thereof.

In a further aspect, the compound is:

3. Prophetic Examples

The following compound examples are prophetic, and can be prepared usingthe synthesis methods described herein above and other general methodsas needed as would be known to one skilled in the art. Thus, in oneaspect, a compound can be:

or a salt thereof.

C. Methods of Making the Disclosed Compounds

In one aspect, disclosed are methods of making a disclosed compound.

Thus, in one aspect, disclosed are methods of making a compound having astructure represented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein R² isselected from hydrogen, C1-C8 alkyl substituted with 0-1 phenyl groups,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar²,—(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl groups; wherein Ar², when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³ when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl, or a salt thereof, the methodcomprising the step of reacting a phosphonate derivative having astructure represented by a formula:

wherein R⁴ is C1-C4 alkyl, provided that R² and R⁴ are different, or asalt thereof, with a nucleophile having a structure represented by aformula:

in the presence of an activating agent and a base.

In a further aspect, the compound has a structure represented by aformula:

wherein n is 0 or 1; wherein A is selected from O, S, and CHR²¹; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from —(C1-C4alkyl)Ar¹ and Ar¹; wherein Ar¹, when present, is selected from aryl andheteroaryl and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl),—OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰,—(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl),—(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b),—NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b), and —N═NR³²; whereinR³⁰, when present, is selected from hydrogen, C1-C8 alkyl, —(C1-C4alkyl)phenyl, phenyl, and a structure represented by a formula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein R² is selected from —(C1-C4 alkyl)Ar² and Ar²; whereinAr², when present, is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OC₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl.

In one aspect, disclosed are methods of making a compound having astructure represented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein Ar² isselected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar⁴ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OC₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl, or a salt thereof, the method comprising the step of reacting aphosphinate derivative having a structure represented by a formula:

wherein R³ is C1-C4 alkyl, or a salt thereof, with a nucleophile havinga structure represented by a formula:

in the presence of an activating agent and a base.

In a further aspect, the compound has a structure represented by aformula:

wherein n is 0 or 1; wherein A is selected from O, S, and CHR²¹; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from —(C1-C4 alkyl)Ar¹and Ar¹; wherein Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(31a)R^(31b), —NH(C═O)NR^(31a)R^(31b),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein Ar³ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl.

In a further aspect, the phosphonate derivative, the nucleophile, theactivating agent, and the base are simultaneously reacted. In a stillfurther aspect, the phosphonate derivative, the nucleophile, theactivating agent, and the base are sequentially reacted.

In a further aspect, the phosphinate derivative, the nucleophile, theactivating agent, and the base are simultaneously reacted. In a stillfurther aspect, the phosphinate derivative, the nucleophile, theactivating agent, and the base are sequentially reacted.

In a further aspect, the phosphonate derivative, the activating agent,and the base react to form a reaction product, and wherein the reactionproduct reacts with the nucleophile.

In a further aspect, the phosphinate derivative, the activating agent,and the base react to form a reaction product, and wherein the reactionproduct reacts with the nucleophile.

As used herein, the term “activating agent” means an agent capable ofreplacing a ligand on a phosphine atom with a desired leaving group.Examples of activating agents include, but are not limited to, triflicanhydride, mesyl chloride, tosyl chloride, oxalyl chloride, thionylchloride, acetic anhydride, benzoic anhydride, and trifluoroaceticanhydride. In a further aspect, the activating agent is triflicanhydride.

Examples of bases that can be used in the disclosed methods include, butare not limited to, piperidine, pyridine, pyrimidine, trimethylamine,imidazole, quinoline, indole, pyrazole, morpholine, N-methylmorpholine,pyrrole, thiazole, 2-iodopyridine, 2-fluoropyridine, 2-chloropyridine,2-MeO-pyridine, and 4-iodopyridine. In a further aspect, the base ispyridine.

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

1. Route I

In one aspect, disclosed organophosphorous compounds can be prepared asshown below.

Compounds are represented in generic form, wherein R is the activatingagent (minus the leaving group), wherein LG is a leaving group, and withother substituents as noted in compound descriptions elsewhere herein. Amore specific example is set forth below.

In one aspect, the synthesis of an organophosphorous compound can beginwith a phosphonate derivative. Phosphonate derivatives are commerciallyavailable or readily prepared by one skilled in the art. Thus, compoundsof type 1.10 and similar compounds can be prepared according to reactionScheme ib above. Compounds of type 1.8 can be prepared by activation ofan appropriate phosphonate derivative, e.g., 1.6 as shown above. Theactivation is carried out in the presence of an appropriate activatingagent, e.g., triflic anhydride, and an appropriate base, e.g., pyridine,in an appropriate solvent, e.g., dichloromethane, for an appropriateperiod of time, e.g., 10 minutes. Compounds of type 1.10 can be preparedby a nucleophilic substitution reaction between an organophosphorouscompound having a leaving group, e.g., 1.8, and an appropriatenucleophile, e.g., 1.9 as shown above. Appropriate nucleophiles arecommercially available or readily prepared by one skilled in the art.The nucleophilic substitution reaction is carried out in an appropriatesolvent, e.g., dichloromethane, for an appropriate period of time, e.g.,30 min. As can be appreciated by one skilled in the art, the abovereaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similarto compounds of type 1.1, 1.2, 1.3, and 1.4), can be substituted in thereaction to provide substituted organophosphorous compounds similar toFormula 1.4.

2. Route II

In one aspect, disclosed organophosphorous compounds can be prepared asshown below.

Compounds are represented in generic form, wherein R is the activatingagent (minus the leaving group), wherein LG is a leaving group, and withother substituents as noted in compound descriptions elsewhere herein. Amore specific example is set forth below.

In one aspect, the synthesis of an organophosphorous compound can beginwith a phosphinate derivative. Phosphinate derivatives are commerciallyavailable or readily prepared by one skilled in the art. Thus, compoundsof type 2.10 and similar compounds can be prepared according to reactionScheme iib above. Compounds of type 2.8 can be prepared by activation ofan appropriate phosphinate derivative, e.g., 2.6 as shown above. Theactivation is carried out in the presence of an appropriate activatingagent, e.g., triflic anhydride, and an appropriate base, e.g., pyridine,in an appropriate solvent, e.g., dichloromethane, for an appropriateperiod of time, e.g., 10 minutes. Compounds of type 2.10 can be preparedby a nucleophilic substitution reaction between an organophosphorouscompound having a leaving group, e.g., 2.8, and an appropriatenucleophile, e.g., 2.9 as shown above. Appropriate nucleophiles arecommercially available or readily prepared by one skilled in the art.The nucleophilic substitution reaction is carried out in an appropriatesolvent, e.g., dichloromethane, for an appropriate period of time, e.g.,30 min. As can be appreciated by one skilled in the art, the abovereaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similarto compounds of type 2.1, 2.2, 2.3, and 2.4), can be substituted in thereaction to provide substituted organophosphorous compounds similar toFormula 2.4.

D. EXAMPLES

It was hypothesized that the terminal oxygen P(V)═O ofdialkylphosphonates 1 could be activated by Tf₂O to afford a phosphoniumintermediate I (FIG. 3; Kenny et al. (2015) Chem. Commun. 51: 16561;Imamoto et al. (2001) Org. Lett. 3: 87), which is then converted toTfO-substituted phosphonate intermediate II via nucleophilicsubstitution reaction (Rajendran et al. (2015) J. Am. Chem. Soc. 137:9375). Finally, it was envisioned that the phosphonate intermediate IIin presence of pyridine could be transformed to a highly reactivepyridinium phosphonate intermediate III (Sigurdsson and Stromberg (2002)J. Chem. Am. Soc. Perkin Trans. 2, 1682; Li et al. (2015) TetrahedronLett. 56: 4694; Ladame et al. (2001) Phosphorus Sulfiur Silicon Relat.Elem. 174: 37). With this idea in mind, the development of newelectrophilic P-species using the chemically inert dialkylphosphonateswas explored or a facile synthesis of mixed phosphonates. Herein, ametal-free, chloride reagent-free, and Tf₂O-mediated activation ofphosphonates for the synthesis of mixed phosphonates via directaryloxylation/alkyloxylation strategies is described.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, and/or methods disclosed herein are made and evaluated, andare intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers (e.g., amounts, temperature, etc.), but some errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, temperature is in ° C. or is at ambienttemperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Chemistry Experimental a. General Experimental

All reactions were carried out under air atmosphere in oven-driedglassware with magnetic stirring bar. Dry solvents (THF, toluene, andDCM) were obtained by solvent purification system under argon. Allcommercially available reagents were used as received without furtherpurification. The tubes used for the reaction were showed in Figure S1.Purification of reaction products was carried out by flash columnchromatography using silica gel 60 (230-400 mesh). Analytical thin layerchromatography was performed on 0.25 mm aluminum-backed silica gel 60-Fplates. Visualization was accompanied with UV light and KMnO₄ solution.Concentration under reduced pressure refers to the removal of volatilesusing a rotary evaporator attached to a dry diaphragm pump (10-15 mm Hg)followed by pumping to a constant weight with an oil pump (<300 mTorr).Infrared (IR) spectra were recorded on an IR spectrometer with KBrwafers or a film on KBr plate. High-resolution mass spectra (HRMS) wererecorded on LCMS-IT-TOF mass spectrometer using ESI (electrosprayionization) or APCI (Atmospheric Pressure Chemical Ionization). ¹H NMRspectra were recorded in CDCl₃ on 400 MHz NMR spectrometer. The ¹Hchemical shifts are referenced to residual solvent signals at δ 7.26(CHCl₃) or δ 0.00 (TMS). ¹H NMR coupling constants (J) are reported inHertz (Hz) and multiplicities are indicated as follows: s (singlet), bs(broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet),dd (doublet of doublets), dt (doublet of triplets), td (triplet ofdoublets), tt (triplet of triplets). ¹³C NMR spectra were protondecoupled and recorded in CDCl₃ on 100.5 MHz NMR spectrometer. The ¹³Cchemical shifts are referenced to solvent signals at δ 77.16 (CDCl₃).³¹P NMR spectra were proton decoupled and recorded in CDCl₃ on 162 MHzNMR spectrometer. ³¹P chemical shifts are reported relative to 85% H₃PO₄(0.00 ppm) as an external standard.

b. General Procedure for the Synthesis of Mixed Phosphonates

Ethyl phenyl benzylphosphonate (3a as example): To a solution of diethylbenzylphosphonate 1a (45.4 mg, 0.2 mmol), Tf₂O (50.5 μL, 0.3 mmol) inDCM (1.0 mL) was added pyridine (32 μL, 0.4 mmol). After the mixture wasstirred for 10 min, phenol (46.5 mg, 0.5 mmol) was added to vial underair condition. After being stirred for another 30 min at roomtemperature, the resulting solution was directly concentrated to givethe crude material which was then purified by column chromatography onsilica gel (PE/EA=3:1) to afford ethyl phenyl benzylphosphonate (3a).

i. Ethyl phenyl benzylphosphonate (3A)

50.8 mg, 92%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3032, 2981, 2908, 2593, 1489, 1261, 1207, 1037, 925; ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.23 (m, 7H), 7.16-7.08 (m, 3H), 4.11-4.04(m, 2H), 3.31 (dd, J=21.6, 2.8 Hz, 2H), 1.20 (t, J=6.8 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 150.6 (d, J=8.9 Hz), 130.9 (d, J=8.9 Hz), 129.9 (d,J=7.4 Hz), 129.6, 128.6 (d, J=3.0 Hz), 127.1 (d, J=3.7 Hz), 124.8 (d,J=1.5 Hz), 120.5 (d, J=4.5 Hz), 63.0 (d, J=6.7 Hz), 33.8 (d, J=138.4Hz), 16.2 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 23.8 ppm.

ii. Ethyl phenyl 4-methylbenzylphosphonate (3B)

52.8 mg, 91%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2924, 1593, 1489, 1261, 1207, 1037, 925; ¹H NMR (400MHz, CDCl₃) δ 7.29 (t, J=8.0 Hz, 2H), 7.27 (dd, J=7.6, 1.6 Hz, 2H),7.16-7.08 (m, 5H), 4.14-4.00 (m, 2H), 3.28 (d, J=21.6 Hz, 2H), 2.33 (s,3H), 1.20 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d,J=8.9 Hz), 136.7 (d, J=3.7 Hz), 129.9 (d, J=7.4 Hz), 129.7 (d, J=6.7Hz), 129.6, 129.3 (d, J=3.0 Hz), 127.7 (d, J=9.7 Hz), 124.7, 120.5 (d,J=3.7 Hz), 63.0 (d, J=6.7 Hz), 33.3 (d, J=138.4 Hz), 21.0, 16.2 (d,J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.16 ppm.

iii. Ethyl phenyl 4-methoxybenzylphosphonate (3C)

57.5 mg, 94%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3039, 2981, 2908, 1593, 1489, 1249, 1207, 1037, 925; ¹HNMR (400 MHz, CDCl₃) δ 7.32-7.21 (m, 4H), 7.15-7.09 (m, 3H), 6.87-6.83(m, 2H), 4.14-4.00 (m, 2H), 3.25 (d, J=21.2, 2.8 Hz, 2H), 1.20 (dt,J=6.8, 0.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 158.7 (d, J=3.8 Hz),150.6 (d, J=9.0 Hz), 130.9 (d, J=6.7 Hz), 129.6, 124.7 (d, J=1.5 Hz),122.7 (d, J=8.9 Hz), 120.5 (d, J=3.7 Hz), 114.1 (d, J=3.0 Hz), 63.0 (d,J=7.4 Hz), 55.2, 32.7 (d, J=138.4 Hz), 16.3 (d, J=5.3 Hz); ³¹P NMR (162MHz, CDCl₃): δ 24.23 ppm.

iv. Ethyl phenyl 4-chlorobenzylphosphonate (3D)

54.6 mg, 88%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2981, 2908, 1593, 1489, 1261, 1207, 1037, 925; ¹HNMR (400 MHz, CDCl₃) δ 7.33-7.23 (m, 6H), 7.17-7.14 (m, 1H), 7.13-7.09(m, 2H), 4.17-4.01 (m, 2H), 3.28 (dd, J=22.0, 2.4 Hz, 2H), 1.21 (t,J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.4 (d, J=8.9 Hz), 133.1(d, J=4.4 Hz), 131.2 (d, J=6.7 Hz), 129.7, 129.5 (d, J=8.9 Hz), 128.7(d, J=3.0 Hz), 124.9, 120.4 (d, J=4.4 Hz), 63.2 (d, J=6.7 Hz), 33.1 (d,J=138.4 Hz), 16.2 (d, J=5.2 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 23.00 ppm.

v. Ethyl phenyl 4-bromobenzylphosphonate (3E)

63.7 mg, 90%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.44 (dd, J=8.4, 0.8 Hz, 2H), 7.36-7.27 (m, 2H),7.19 (dd, J=8.4, 2.4 Hz, 2H), 7.17-7.14 (m, 1H), 7.13-7.08 (m, 2H),4.13-4.01 (m, 2H), 3.26 (dd, J=22.0, 2.0 Hz, 2H), 1.21 (t, J=7.2 Hz,3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.4 (d, J=8.9 Hz), 131.7 (d, J=3.0Hz), 131.5 (d, J=6.7 Hz), 130.1 (d, J=9.7 Hz), 129.7, 124.9 (d, J=1.5Hz), 121.2 (d, J=4.5 Hz), 120.4 (d, J=4.4 Hz), 63.2 (d, J=6.7 Hz), 33.2(d, J=139.2 Hz), 16.2 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 22.80ppm. Spectroscopy data of this compound matches with the data reportedin the corresponding reference (Fafianas-Mastral and Feringa (2014) J.Am. Chem. Soc. 136: 9894).

vi. Ethyl phenyl 4-(trifluoromethyl)benzylphosphonate (3F)

58.5 mg, 86%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3066, 2985, 2912, 1593, 1489, 1327, 1261, 1165, 1126,1037, 929; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=8.4 Hz, 2H), 7.44 (dd,J=8.4, 2.0 Hz, 2H), 7.33-7.27 (m, 2H), 7.18-7.08 (m, 3H), 4.18-4.04 (m,2H), 3.37 (d, J=22.4 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 150.4 (d, J=8.9 Hz), 135.3 (dd, J=10.4, 1.5 Hz), 130.2 (d,J=6.7 Hz), 129.7, 129.4 (dd, J=32.0, 3.7 Hz), 125.5 (q, J=2.7 Hz),125.0, 124.1 (dd, J=284.3, 1.5 Hz), 120.3 (d, J=4.5 Hz), 63.3 (d, J=7.4Hz), 33.7 (d, J=138.4 Hz), 16.2 (d, J=5.2 Hz); ³¹P NMR (162 MHz, CDCl₃):δ 22.41 ppm.

vii. Ethyl phenyl (naphthalen-1-ylmethyl)phosphonate (3G)

58.6 mg, 90%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3043, 2981, 2927, 1593, 1489, 1261, 1207, 1037, 925; ¹HNMR (400 MHz, CDCl₃) δ 8.11 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H),7.78 (dd, J=8.4, 2.4 Hz, 1H), 7.57-7.40 (m, 4H), 7.26 (t, J=7.6 Hz, 1H),7.14-7.06 (m, 3H), 4.02-3.93 (m, 2H), 3.58 (d, J=21.6 Hz, 2H), 1.06 (t,J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=8.9 Hz), 133.9(d, J=3.0 Hz), 132.0 (d, J=5.3 Hz), 129.6, 128.7 (d, J=6.7 Hz), 128.6,128.0 (d, J=3.8 Hz), 127.4 (d, J=9.6 Hz), 126.2 (d, J=1.5 Hz), 125.8,125.4 (d, J=3.7 Hz), 124.7, 124.3 (d, J=1.5 Hz), 63.2 (d, J=7.5 Hz),30.8 (d, J=139.2 Hz), 16.1 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ23.48 ppm.

viii. Ethyl phenyl hexylphosphonate (3H)

48.1 mg, 89%; as a colorless oil; R₁-0.40 (ν_(Hexane)/ν_(EA)=2:1); IR ν(KBr, cm⁻¹) 3066, 2951, 2931, 1593, 1489, 1257, 1211, 1041, 921; ¹H NMR(400 MHz, CDCl₃) δ 7.33 (t, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.15(t, J=7.2 Hz, 1H), 4.27-4.07 (m, 2H), 1.93-1.83 (m, 2H), 1.74-1.62 (m,2H), 1.45-1.35 (m, 2H), 1.34-1.24 (m, 7H), 0.88 (t, J=6.8 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 150.7 (d, J=8.2 Hz), 129.6, 124.7, 120.5 (d,J=4.5 Hz), 62.2 (d, J=7.5 Hz), 31.2 (d, J=1.5 Hz), 30.1 (d, J=17.2 Hz),25.7 (d, J=139.9 Hz), 22.3, 22.2 (d, J=6.0 Hz), 16.3 (d, J=5.9 Hz),14.0; ³¹P NMR (162 MHz, CDCl₃): δ 30.29 ppm.

ix. Ethyl phenyl ethylphosphonate (3I)

38.5 mg, 90%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3066, 2981, 2943, 1593, 1489, 1257, 1207, 1045, 921; ¹HNMR (400 MHz, CDCl₃) δ 7.33 (t, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H),7.15 (t, J=7.6 Hz, 1H), 4.28-4.08 (m, 2H), 1.96-1.84 (m, 2H), 1.33-1.19(m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=8.9 Hz), 129.7, 124.7,120.4 (d, J=3.7 Hz), 62.3 (d, J=6.7 Hz), 18.9 (d, J=142.2 Hz), 16.3 (d,J=5.9 Hz), 6.5 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.30 ppm.

x. Ethyl Phenyl Methylphosphonate (3J)

35.8 mg, 85%; as a colorless oil; R_(f) 0.10 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3066, 2985, 2927, 1593, 1489, 1315, 1246, 1207, 1041, 933;¹H NMR (400 MHz, CDCl₃) δ 7.34 (t, J=8.4 Hz, 2H), 7.23-7.14 (m, 3H),4.29-4.09 (m, 2H), 1.63 (d, J=17.6 Hz, 2H), 1.32 (t, J=7.2 Hz, 6H); ¹³CNMR (100.5 MHz, CDCl₃) δ 150.5 (d, J=8.1 Hz), 129.7, 124.9, 120.5 (d,J=4.5 Hz), 62.4 (d, J=6.7 Hz), 16.3 (d, J=6.0 Hz), 11.4 (d, J=144.3 Hz);³¹p NMR (162 MHz, CDCl₃): δ 28.18 ppm. Spectroscopy data of the thiscompound matches with the data reported in the corresponding reference(Fañanás-Mastral and Feringa (2014) J. Am. Chem. Soc. 136: 9894).

xi. Methyl Phenyl Phenylphosphonate (3K)

40.3 mg, 81%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2951, 2854, 1593, 1489, 1261, 1207, 1130, 1041, 929;¹H NMR (400 MHz, CDCl₃) δ 7.92-7.84 (m, 2H), 7.61-7.55 (m, 1H),7.51-7.44 (m, 2H), 7.31-7.26 (m, 2H), 7.19-7.10 (m, 3H), 3.87 (dd,J=11.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.5 (d, J=7.4 Hz),132.9 (d, J=3.7 Hz), 132.0 (d, J=9.6 Hz), 129.6, 128.6 (d, J=14.9 Hz),126.9 (d, J=190.6 Hz), 124.9, 120.5 (d, J=4.5 Hz), 53.1 (d, J=5.9 Hz);³¹P NMR (162 MHz, CDCl₃): δ 17.45 ppm.

xii. Ethyl phenyl phenylphosphonate (3L)

47.7 mg, 91%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.92-7.84 (m, 2H), 7.59-7.54 (m, 1H), 7.50-7.44(m, 2H), 7.30-7.24 (m, 2H), 7.18-7.09 (m, 3H), 4.32-4.18 (m, 2H), 1.35(dt, J=7.2, 0.4 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=7.4Hz), 132.7 (d, J=3.0 Hz), 132.0 (d, J=9.7 Hz), 129.6, 128.5 (d, J=15.6Hz), 127.7 (d, J=189.8 Hz), 124.8, 120.5 (d, J=3.7 Hz), 62.8 (d, J=6.0Hz), 16.3 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 16.05 ppm.Spectroscopy data of the this compound matches with the data reported inthe corresponding reference (Fafianas-Mastral and Feringa (2014) J. Am.Chem. Soc. 136: 9894).

xiii. Isopropyl phenyl phenylphosphonate (3M)

51.3 mg, 93%; as a colorless oil; R_(f) 0.40 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2981, 2931, 1593, 1489, 1257, 1207, 1134, 991, 925;¹H NMR (400 MHz, CDCl₃) δ 7.91-7.84 (m, 2H), 7.58-7.52 (m, 1H),7.49-7.43 (m, 2H), 7.30-7.24 (m, 2H), 7.18-7.13 (m, 2H), 7.11 (dt,J=7.2, 0.8 Hz, 1H), 4.94-4.82 (m, 1H), 1.37 (d, J=6.0 Hz, 3H), 1.32 (d,J=6.0 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=7.4 Hz), 132.5(d, J=3.0 Hz), 131.9 (d, J=10.4 Hz), 129.5, 128.5 (d, J=190.5 Hz), 128.4(d, J=15.6 Hz), 124.7 (d, J=1.5 Hz), 120.6 (d, J=4.5 Hz), 72.0 (d, J=6.0Hz), 23.9 (d, J=4.4 Hz), 23.8 (d, J=3.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ14.96 ppm.

xiv. Butyl phenyl phenylphosphonate (3N)

51.7 mg, 85%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2985, 2873, 1593, 1489, 1261, 1207, 1130, 1022, 929;¹H NMR (400 MHz, CDCl₃) δ 7.91-7.84 (m, 2H), 7.59-7.54 (m, 1H),7.50-7.44 (m, 2H), 7.30-7.24 (m, 2H), 7.18-7.09 (m, 3H), 4.24-4.11 (m,2H), 1.74-1.64 (m, 2H), 1.45-1.34 (m, 2H), 0.90 (t, J=7.2 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=7.5 Hz), 132.7 (d, J=2.9 Hz), 132.0(d, J=9.7 Hz), 129.6, 128.5 (d, J=15.6 Hz), 127.7 (d, J=189.8 Hz),124.7, 120.5 (d, J=4.5 Hz), 66.5 (d, J=5.9 Hz), 32.3 (d, J=6.7 Hz),18.7, 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 16.04 ppm.

xv. Ethyl phenyl (4-nitrophenyl)phosphonate (3O)

17.0 mg, 28%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3066, 2985, 2931, 1593, 1527, 1489, 1350, 1265, 1203,1126, 1033, 929; ¹H NMR (400 MHz, CDCl₃) δ 7.92-7.84 (m, 2H), 7.59-7.54(m, 1H), 7.50-7.44 (m, 2H), 7.30-7.24 (m, 2H), 7.18-7.09 (m, 3H),4.32-4.18 (m, 2H), 1.35 (dt, J=7.2, 0.4 Hz, 3H); ¹³C NMR (100.5 MHz,CDCl₃) δ 150.5, 150.0 (d, J=7.4 Hz), 134.8 (d, J=189.0 Hz), 133.2 (d,J=10.4 Hz), 129.8, 125.3 (d, J=1.5 Hz), 123.4 (d, J=15.6 Hz), 120.4 (d,J=4.5 Hz), 63.7 (d, J=6.0 Hz), 16.3 (d, J=6.0 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 12.14 ppm.

xvi. Ethyl phenyl (2-bromoethyl)phosphonate (3P)

53.0 mg, 91%; as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.32(m, 2H), 7.22-7.16 (m, 3H), 4.30-4.10 (m, 2H), 3.65-3.57 (m, 2H),2.60-2.50 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ150.1 (d, J=8.2 Hz), 129.9, 125.2, 120.4 (d, J=4.5 Hz), 63.0 (d, J=6.7Hz), 30.7 (d, J=134.7 Hz), 23.3, 16.3 (d, J=6.0 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 23.00 ppm. Spectroscopy data of the this compound matches withthe data reported in the corresponding reference (Fafianas-Mastral andFeringa (2014) J. Am. Chem. Soc. 136: 9894).

xvii. Ethyl phenyl allylphosphonate (3Q)

41.1 mg, 91%; as a colorless oil; R_(f) 0.17 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3070, 2981, 2904, 1593, 1489, 1265, 1207, 1037, 925; ¹HNMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.23-7.17 (m, 3H), 5.92-5.79(m, 1H), 5.30-5.22 (m, 2H), 4.28-4.11 (m, 2H), 2.82-2.73 (m, 2H), 1.30(t, J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.5 (d, J=8.2 Hz),129.7, 126.8 (d, J=11.1 Hz), 124.9 (d, J=1.5 Hz), 120.6 (d, J=6.7 Hz),120.5 (d, J=3.7 Hz), 62.8 (d, J=7.4 Hz), 31.7 (d, J=139.2 Hz), 16.3 (d,J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.54 ppm.

xviii. Ethyl (4-methoxyphenyl) allylphosphonate (3R)

47.6 mg, 93%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3082, 2981, 2908, 1504, 1253, 1203, 1033, 933; ¹H NMR (400MHz, CDCl₃) δ 7.15-7.10 (m, 2H), 6.86-6.81 (m, 2H), 5.91-5.78 (m, 1H),5.29-5.22 (m, 2H), 4.26-4.10 (m, 2H), 3.78 (s, 3H), 2.79-2.70 (m, 2H),1.30 (t, J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 156.6, 144.0 (d,J=8.2 Hz), 126.9 (d, J=11.9 Hz), 121.4 (d, J=4.5 Hz), 120.5 (d, J=14.9Hz), 114.6, 62.8 (d, J=7.4 Hz), 55.6, 31.5 (d, J=139.1 Hz), 16.3 (d,J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.89 ppm.

xix. (E)-Ethyl phenyl styrylphosphonate (3S)

50.7 mg, 88%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2931, 1616, 1593, 1489, 1261, 1207, 1037, 929; ¹HNMR (400 MHz, CDCl₃) δ 7.59 (dd, J=23.2, 17.6 Hz, 1H), 7.52-7.48 (m,2H), 7.41-7.36 (m, 3H), 7.34-7.29 (m, 2H), 7.25-7.21 (m, 2H), 7.17-7.12(m, 1H), 6.36 (dd, J=18.4, 17.6 Hz, 1H), 4.32-4.18 (m, 2H), 1.37 (dt,J=7.6, 0.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.5 (d, J=7.4 Hz),149.9 (d, J=6.7 Hz), 134.6 (d, J=23.9 Hz), 130.5, 129.7, 128.9, 127.8,124.8 (d, J=1.5 Hz), 120.5 (d, J=4.5 Hz), 113.1 (d, J=193.5 Hz), 62.6(d, J=6.0 Hz), 16.3 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 16.94ppm.

xx. Ethyl (4-methoxyphenyl) (phenylethynyl)phosphonate (3T)

60.0 mg, 95%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2985, 2904, 2187, 1504, 1273, 1199, 1033, 941; ¹HNMR (400 MHz, CDCl₃) δ 7.53-7.49 (m, 2H), 7.45 (tt, J=7.6, 2.4 Hz, 1H),7.39-7.33 (m, 2H), 7.24-7.19 (m, 2H), 6.89-6.84 (m, 2H), 4.38-4.29 (m,2H), 1.44 (dt, J=7.2, 0.4 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 157.0(d, J=1.5 Hz), 143.5 (d, J=6.7 Hz), 132.6 (d, J=3.0 Hz), 130.9, 128.6,121.6 (d, J=4.5 Hz), 119.2 (d, J=6.0 Hz), 114.7 (d, J=1.5 Hz), 100.4 (d,J=53.6 Hz), 77.8 (d, J=307.4 Hz), 64.0 (d, J=5.2 Hz), 55.6, 16.1 (d,J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ−8.74 ppm.

xxi. Ethyl (4-methoxyphenyl) (2E, 4E)-undeca-2,4-dien-1-ylphosphonate(3U)

43.3 mg, 64%; as a colorless oil; R_(f) 0.25 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2954, 2927, 2858, 1504, 1249, 1199, 1037, 933; ¹H NMR (400MHz, CDCl₃) δ 7.11 (dd, J=9.2, 1.2 Hz, 2H), 6.86-6.80 (m, 2H), 6.19-6.11(m, 1H), 6.07-5.98 (m, 1H), 5.70-5.61 (m, 1H), 5.58-5.47 (m, 1H),4.26-4.08 (m, 2H), 3.78 (s, 3H), 2.74 (dd, J=22.4, 7.6 Hz, 2H), 2.07(dd, J=14.4, 7.2 Hz, 2H), 1.42-1.21 (m, 9H), 0.89 (t, J=6.8 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 156.6, 144.0 (d, J=8.9 Hz), 135.9 (d, J=4.9Hz), 135.2 (d, J=4.4 Hz), 129.3 (d, J=4.4 Hz), 121.4 (d, J=3.8 Hz),118.4 (d, J=12.7 Hz), 114.6, 62.8 (d, J=7.4 Hz), 55.6, 32.5, 31.4, 30.4(d, J=139.9 Hz), 28.8 (d, J=1.5 Hz), 22.5, 16.3 (d, J=5.2 Hz), 14.0; ³¹PNMR (162 MHz, CDCl₃): δ 25.13 ppm.

xxii. Ethyl phenyl (1-phenylethyl)phosphonate (3V)

44.1 mg, 76% with dr=1.6:1; as a colorless oil; R₁ 0.20(ν_(Hexane)/ν_(EA)=2:1); IR ν (KBr, cm⁻¹) 3028, 2978, 2935, 1593, 1489,1257, 1207, 1026, 925; ¹H NMR (400 MHz, CDCl₃, * denotes minor rotamerpeaks) δ 7.41-7.36 (m, 2H), 7.36-7.21 (m, 5H), 7.15-7.06 (m, 2H),7.02-7.08 (m, 1H), 4.19-4.00* (m, 2H), 3.99-3.83 (m, 2H), 3.43-3.36* (m,1H), 3.36-3.30 (m, 1H), 1.71* (dd, J=7.2, 2.0 Hz, 2H), 1.66 (dd, J=7.2,2.0 Hz, 2H), 1.23* (t, J=7.2 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 150.9 (d, J=3.7 Hz), 150.8 (d, J=3.7 Hz), 137.5 (d,J=7.4 Hz), 137.3 (d, J=7.5 Hz), 129.6, 129.5, 128.8 (d, J=3.7 Hz), 128.7(d, J=3.7 Hz), 128.52, 128.50, 127.3 (d, J=3.7 Hz), 127.2 (d, J=3.7 Hz),127.7, 124.7, 120.5 (d, J=4.5 Hz), 120.4 (d, J=3.7 Hz), 63.4 (d, J=7.4Hz), 63.0 (d, J=7.4 Hz), 38.7 (d, J=137.7 Hz), 38.5 (d, J=137.7 Hz),16.3 (d, J=5.9 Hz), 16.1 (d, J=5.2 Hz), 15.7 (d, J=4.4 Hz), 15.6 (d,J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 27.30, 27.00 ppm.

xxiii. Ethyl phenyl (furan-2-ylmethyl)phosphonate (3W)

44.2 mg, 83%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2908, 1720, 1593, 149, 1265, 1207, 1037, 933; ¹H NMR(400 MHz, CDCl₃) δ 7.35-7.36 (m, 1H), 7.34-7.28 (m, 2H), 7.18-7.13 (m,3H), 6.36-6.33 (m, 1H), 6.30-6.27 (m, 1H), 4.24-4.09 (m, 2H), 3.40 (d,J=20.8 Hz), 1.27 (dt, J=7.2, 0.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ150.4, 144.9 (d, J=9.6 Hz), 142.1 (d, J=3.0 Hz), 129.7, 125.0 (d, J=1.5Hz), 120.5 (d, J=4.4 Hz), 110.8 (d, J=3.0 Hz), 108.6 (d, J=7.4 Hz), 63.3(d, J=6.7 Hz), 26.7 (d, J=144.3 Hz), 16.2 (d, J=5.9 Hz); ³¹P NMR (162MHz, CDCl₃): δ 20.49 ppm.

xxiv. O-Ethyl O,S-diphenyl phosphorothioate (3X)

47.6 mg, 81%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2985, 2904, 1589, 1489, 1265, 1199, 1022, 929; ¹HNMR (400 MHz, CDCl₃) δ 7.55-7.50 (m, 2H), 7.40-7.29 (m, 5H), 7.17 (t,J=8.0 Hz, 3H), 4.37-4.22 (m, 2H), 1.34 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 150.4 (d, J=7.4 Hz), 134.9 (d, J=5.2 Hz), 129.6, 129.4 (d,J=3.0 Hz), 129.3 (d, J=3.7 Hz), 125.7 (d, J=6.7 Hz), 125.3 (d, J=1.5Hz), 120.4 (d, J=5.2 Hz), 64.8 (d, J=6.0 Hz), 16.0 (d, J=7.5 Hz); ³¹PNMR (162 MHz, CDCl₃): δ 19.53 ppm.

xxv. Ethyl p-tolyl benzylphosphonate (4A)

54.0 mg, 88%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3032, 2981, 108, 145, 1261, 1207, 1037, 925; ¹H NMR (400MHz, CDCl₃) δ 7.35-7.23 (m, 5H), 7.10-7.06 (m, 2H), 7.00-6.96 (m, 2H),4.13-3.99 (m, 2H), 3.30 (dd, J=21.6, 3.2 Hz, 2H), 2.30 (s, 3H), 1.19(dt, J=6.8, 0.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.3 (d, J=8.9Hz), 134.3 (d, J=1.5 Hz), 131.0 (d, J=8.9 Hz), 130.1 (d, J=1.4 Hz),129.9 (d, J=6.7 Hz), 128.6 (d, J=2.9 Hz), 127.0 (d, J=3.7 Hz), 120.2 (d,J=4.5 Hz), 63.0 (d, J=7.5 Hz), 33.7 (d, J=138.4 Hz), 20.7, 16.0 (d,J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 23.89 ppm.

xxvi. Ethyl (4-methoxyphenyl) benzylphosphonate (4B)

55.0 mg, 90%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2908, 1504, 1442, 1257, 1203, 1037, 933; ¹H NMR (400MHz, CDCl₃) δ 7.32 (d, J=4.4 Hz, 4H), 7.30-7.24 (m, 1H), 7.04-6.99 (m,2H), 6.80 (d, J=8.8 Hz, 2H), 4.13-3.98 (m, 2H), 3.77 (s, 3H), 3.29 (dd,J=21.6, 2.8 Hz, 2H), 2.30 (s, 3H), 1.19 (dt, J=7.2, 0.8 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 156.5, 144.0 (d, J=8.9 Hz), 131.0 (d, J=9.7 Hz),129.9 (d, J=6.7 Hz), 128.6 (d, J=3.0 Hz), 127.0 (d, J=3.7 Hz), 121.3 (d,J=3.7 Hz), 114.6, 63.0 (d, J=6.7 Hz), 55.6, 33.6 (d, J=138.4 Hz), 16.2(d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.17 ppm;

xxvii. 4-bromophenyl ethyl benzylphosphonate (4C)

63.5 mg, 89%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2981, 2908, 1485, 1261, 1215, 1037, 921; ¹H NMR (400MHz, CDCl₃) δ 7.41-7.36 (m, 2H), 7.34-7.24 (m, 5H), 6.99-6.94 (m, 2H),4.15-4.00 (m, 2H), 3.31 (dd, J=21.6, 1.6 Hz, 2H), 1.21 (dt, J=7.2, 0.4Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 149.7 (d, J=8.2 Hz), 132.6, 130.6(d, J=9.7 Hz), 129.9 (d, J=6.7 Hz), 128.6 (d, J=3.0 Hz), 127.2 (d, J=3.8Hz), 122.2 (d, J=4.4 Hz), 117.7, 63.2 (d, J=7.5 Hz), 33.8 (d, J=137.7Hz), 16.2 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.16 ppm.

xxviii. Ethyl (4-iodophenyl) benzylphosphonate (4D)

68.2 mg, 85%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 2981, 2908, 1481, 1261, 1215, 1037, 921; ¹H NMR (400MHz, CDCl₃) δ 7.60-7.55 (m, 2H), 7.34-7.24 (m, 5H), 6.87-6.82 (m, 2H),4.15-4.00 (m, 2H), 3.31 (dd, J=21.6, 1.6 Hz, 2H), 1.21 (dt, J=7.2, 0.4Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.5 (d, J=8.9 Hz), 138.6, 130.6(d, J=9.7 Hz), 129.9 (d, J=6.7 Hz), 128.6 (d, J=3.0 Hz), 127.2 (d, J=4.8Hz), 122.6 (d, J=3.7 Hz), 88.4 (d, J=1.5 Hz), 63.2 (d, J=6.7 Hz), 33.8(d, J=137.6 Hz), 16.2 (d, J=5.2 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.10ppm.

xxix. Ethyl (4-,itrophenyl) benzylphosphonate (4E)

59.3 mg, 92%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3082, 2985, 2912, 1612, 1589, 1519, 1492, 1346, 1265,1226, 1033, 918; ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.13 (m, 2H), 7.36-7.25(m, 5H), 7.23-7.17 (m, 2H), 4.21-4.07 (m, 2H), 3.42-3.32 (m, 2H),1.29-1.23 (m, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.7 (d, J=8.2 Hz),144.4, 130.0 (d, J=9.7 Hz), 129.9 (d, J=6.7 Hz), 128.8 (d, J=3.7 Hz),127.4 (d, J=3.7 Hz), 125.5, 120.8 (d, J=4.5 Hz), 63.5 (d, J=7.4 Hz),34.0 (d, J=138.4 Hz), 16.2 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ24.57 ppm.

xxx. Ethyl o-tolyl benzylphosphonate (4F)

52.1 mg, 90%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=3:1); IRν (KBr, cm⁻¹) 3032, 2981, 2912, 1585, 1492, 1454, 1261, 1226, 1180,1037, 929; ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.24 (m, 5H), 7.22 (d, J=8.0Hz, 1H), 7.16-7.08 (m, 2H), 7.03 (t, J=7.6 Hz, 1H), 4.13-3.97 (m, 2H),3.34 (dd, J=21.2, 0.8 Hz, 2H), 2.12 (s, 3H), 1.17 (t, J=6.8 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 149.0 (d, J=9.6 Hz), 131.3, 131.1 (d, J=9.7Hz), 129.9 (d, J=6.7 Hz), 129.5 (d, J=5.9 Hz), 128.5 (d, J=3.0 Hz),127.0 (d, J=3.7 Hz), 126.9 (d, J=1.5 Hz), 124.7, 120.2 (d, J=3.0 Hz),63.2 (d, J=6.7 Hz), 33.9 (d, J=139.2 Hz), 16.2 (d, J=6.7 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 23.74 ppm.

xxxi. Ethyl m-tolyl benzylphosphonate (4G)

53.9 mg, 93%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=3:1); IRν (KBr, cm⁻¹) 2032, 2981, 2912, 1608, 1585, 1489, 1261, 1149, 1037, 952;¹H NMR (400 MHz, CDCl₃) δ 7.35-7.24 (m, 5H), 7.16 (t, J=8.8 Hz, 1H),6.96-6.87 (m, 3H), 4.15-4.00 (m, 2H), 3.31 (dd, J=21.6, 1.6 Hz, 2H),2.30 (s, 3H), 1.20 (dt, J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ150.5 (d, J=8.2 Hz), 139.8, 131.0 (d, J=9.6 Hz), 129.9 (d, J=6.7 Hz),129.3, 128.5 (d, J=2.9 Hz), 127.0 (d, J=3.7 Hz), 125.6, 121.1 (d, J=4.5Hz), 117.3 (d, J=4.4 Hz), 63.0 (d, J=6.7 Hz), 33.7 (d, J=138.5 Hz),21.3, 16.2 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 23.71 ppm.

xxxii. Ethyl (3-(trifluoromethyl)phenyl) benzylphosphonate (4H)

59.9 mg, 83%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=3:1); IRν (KBr, cm⁻¹) 3059, 2985, 2866, 1593, 1492, 1450, 1327, 1261, 1168,1130, 1037, 948; ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.37 (m, 2H), 7.39-7.26(m, 7H), 4.16-4.05 (m, 2H), 3.35 (d, J=21.6 Hz, 2H), 1.23 (dt, J=7.2,1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.7 (d, J=8.9 Hz), 132.0 (d,J=32.7 Hz), 130.4 (d, J=9.7 Hz), 130.2, 129.9 (d, J=6.7 Hz), 128.7 (d,J=3.7 Hz), 127.3 (d, J=3.7 Hz), 123.9 (d, J=3.0 Hz), 123.3 (d, J=271.6Hz), 121.5 (d, J=3.0 Hz), 117.7 (m), 63.3 (d, J=7.5 Hz), 33.9 (d,J=137.7 Hz), 16.2 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 26.98 ppm.

xxxiii. 2,4-Dichlorophenyl ethyl benzylphosphonate (4I)

52.9 mg, 77%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=3:1); IRν (KBr, cm⁻¹) 3032, 2962, 2927, 1477, 1269, 1234, 1099, 1033, 921; ¹HNMR (400 MHz, CDCl₃) δ 7.39-7.37 (m, 1H), 7.36-7.25 (m, 5H), 7.15-7.09(m, 2H), 4.19-4.05 (m, 2H), 3.38 (d, J=22.0 Hz, 2H), 1.22 (t, J=7.2 Hz,3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 145.6 (d, J=8.2 Hz), 130.3 (d, J=5.2Hz), 130.2 (d, J=3.0 Hz), 130.1, 129.9 (d, J=6.7 Hz), 128.7 (d, J=3.8Hz), 127.8, 127.3 (d, J=3.7 Hz), 126.4 (d, J=5.9 Hz), 122.7 (d, J=2.3Hz), 63.5 (d, J=7.5 Hz), 34.0 (d, J=138.4 Hz), 16.2 (d, J=6.0 Hz); ³¹PNMR (162 MHz, CDCl₃): δ 24.98 ppm.

xxxiv. 2,6-Dimethylphenyl ethyl benzylphosphonate (4J)

52.9 mg, 87%; as a colorless oil; R_(f) 0.35 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3032, 2978, 2924, 1473, 1261, 1172, 1037, 929; ¹H NMR (400MHz, CDCl₃) δ 7.40-7.25 (m, 5H), 7.00-6.91 (m, 3H), 3.99-3.84 (m, 2H),3.37 (dd, J=21.6, 5.2 Hz, 2H), 2.25 (s, 6H), 1.05 (dt, J=6.8, 0.4 Hz,3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 147.7 (d, J=11.2 Hz), 131.4 (d, J=9.7Hz), 130.5 (d, J=3.0 Hz), 130.0 (d, J=6.7 Hz), 128.9 (d, J=2.2 Hz),128.5 (d, J=3.0 Hz), 127.0 (d, J=4.5 Hz), 124.8 (d, J=1.5 Hz), 63.4 (d,J=6.7 Hz), 34.3 (d, J=140.7 Hz), 17.3, 16.1 (d, J=6.0 Hz); ³¹P NMR (162MHz, CDCl₃): δ 23.55 ppm.

xxxv. 2,6-Diisopropylphenyl ethyl benzylphosphonate (4K)

40.3 mg, 56%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3028, 2966, 2927, 1442, 1261, 1165, 1037, 929; ¹H NMR (400MHz, CDCl₃) δ 7.40-7.25 (m, 5H), 7.14-7.06 (m, 3H), 3.97-3.81 (m, 2H),3.46-3.30 (m, 4H), 1.15 (dd, J=8.8, 6.8 Hz, 12H), 1.03 (dt, J=6.8, 0.4Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 145.0, 140.8 (d, J=3.0 Hz), 131.4(d, J=9.7 Hz), 130.0 (d, J=6.7 Hz), 128.5 (d, J=3.0 Hz), 127.0 (d, J=3.7Hz), 125.5 (d, J=2.2 Hz), 124.1 (d, J=1.5 Hz), 63.6 (d, J=6.7 Hz), 34.4(d, J=140.7 Hz), 26.9, 23.5 (d, J=26.8 Hz), 16.1 (d, J=5.2 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 22.50 ppm.

xxxvi. [1,1′-biphenyl]-4-yl ethyl benzylphosphonate (4M)

64.0 mg, 91%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 3032, 2981, 1604, 1516, 1485, 1261, 1215, 1168,1037, 925; ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.48 (m, 4H), 7.45-7.40 (m,2H), 7.38-7.25 (m, 6H), 7.19-7.14 (m, 2H), 4.19-4.04 (m, 2H), 3.36 (dd,J=21.6, 1.6 Hz, 2H), 1.24 (dt, J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz,CDCl₃) δ 150.1 (d, J=8.2 Hz), 140.3, 137.9 (d, J=1.5 Hz), 130.9 (d,J=9.6 Hz), 129.9 (d, J=6.7 Hz), 128.8, 128.6 (d, J=3.7 Hz), 128.3,127.2, 127.1 (d, J=3.7 Hz), 127.0, 120.7 (d, J=3.8 Hz), 63.1 (d, J=6.7Hz), 33.8 (d, J=137.7 Hz), 16.3 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃):δ 24.06 ppm.

xxxvii. Ethyl naphthalen-1-yl Benzylphosphonate (4N)

45.4 mg, 70%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 2981, 2908, 1597, 1537, 1462, 1392, 1261, 1230,1083, 1033, 921; ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dd, J=8.4, 1.2 Hz, 1H),7.81 (dd, J=7.6, 1.2 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.51-7.22 (m, 9H),4.02-3.59 (m, 2H), 3.42 (d, J=21.6 Hz, 2H), 1.14 (t, J=7.2 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 146.5 (d, J=9.7 Hz), 134.7, 131.0 (d, J=9.0Hz), 130.0 (d, J=6.7 Hz), 128.6 (d, J=3.0 Hz), 127.7, 127.1 (d, J=3.7Hz), 126.6 (d, J=5.2 Hz), 126.5, 126.1, 125.5, 124.7 (d, J=1.5 Hz),121.8, 115.5 (d, J=3.8 Hz), 63.3 (d, J=6.7 Hz), 33.9 (d, J=138.4 Hz),16.2 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.15 ppm.

xxxviii. Ethyl naphthalen-2-yl phenylphosphonate (4O)

54.3 mg, 87%; as a colorless oil; R_(f) 0.25 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 2981, 1631, 1597, 1508, 1465, 1257, 1211, 1161,1130, 1037, 968; ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.88 (m, 2H), 7.75 (dd,J=15.2, 7.2 Hz, 3H), 7.64 (s, 1H), 7.58-7.53 (m, 1H), 7.49-7.37 (m, 4H),7.33-7.29 (m, 1H), 4.35-4.21 (m, 2H), 1.36 (t, J=7.2 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 148.2 (d, J=7.5 Hz), 133.9, 132.8 (d, J=3.0 Hz),132.0 (d, J=10.5 Hz), 130.8, 129.7, 128.6, 128.5, 127.6 (d, J=14.9 Hz),127.5 (d, J=189.7 Hz), 126.6, 125.3, 120.6 (d, J=4.4 Hz), 117.0 (d,J=5.2 Hz), 63.0 (d, J=5.9 Hz), 16.3 (d, J=6.0 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 16.24 ppm.

xxxix. Ethyl quinolin-6-yl phenylphosphonate (4P)

45.0 mg, 72%; as a colorless oil; R_(f) 0.20 (ν_(DCM)/ν_(MeOH)=98:2); IRν (KBr, cm⁻¹) 3059, 2981, 1624, 1597, 1500, 1261, 1215, 1130, 1037, 968;¹H NMR (400 MHz, CDCl₃) δ 8.85 (dd, J=4.0, 1.6 Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.96-7.89 (m, 2H), 7.67 (t, J=2.0 Hz,1H), 7.63-7.56 (m, 1H), 7.59-7.46 (m, 3H), 7.38 (dd, J=8.4, 4.4 Hz, 1H),4.38-4.23 (m, 2H), 1.38 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ149.8, 148.3 (d, J=6.7 Hz), 145.7, 135.7, 133.0 (d, J=3.0 Hz), 132.0 (d,J=9.6 Hz), 131.3, 128.7, 128.6 (d, J=15.7 Hz), 127.2 (d, J=189.8 Hz),124.1 (d, J=14.1 Hz), 121.6, 116.7 (d, J=4.5 Hz), 63.1 (d, J=6.0 Hz),16.3 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 16.52 ppm.

xl. 4-((Benzyl(ethoxy)phosphoryl)oxy)phenyl octanoate (4Q)

61.7 mg, 74%; as a colorless oil; R_(f) 0.25 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2972, 2858, 1759, 1500, 1454, 1265, 1184, 1141,1037, 925; ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.24 (m, 5H), 7.09 (d, J=8.8Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.07 (br, 2H), 3.32 (d, J=21.2 Hz, 2H),2.53 (t, J=7.6 Hz, 2H), 1.78-1.69 (m, 2H), 1.44-1.24 (m, 8H), 1.20 (t,J=6.4 Hz, 3H), 0.89 (t, J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ172.2, 147.9 (d, J=7.4 Hz), 148.3, 147.4, 130.8 (d, J=8.2 Hz), 129.9 (d,J=5.2 Hz), 128.7, 127.1, 122.6, 121.3, 63.2 (d, J=5.9 Hz), 34.3, 34.0(d, J=137.6 Hz), 31.6, 29.0, 28.9, 24.9, 22.6, 16.3, 14.1; ³¹P NMR (162MHz, CDCl₃): δ 24.15 ppm.

xli. Benzyl (4-((ethoxy(phenyl)phosphoryl)oxy)phenyl) carbonate (4R)

70.7 mg, 86%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2985, 2927, 1759, 1500, 1438, 1381, 1269, 1199,1130, 925; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J=7.2 Hz, 1H), 7.84 (d,J=7.6 Hz, 2H), 7.57 (t, J=7.2 Hz, 1H), 7.50-7.44 (m, 2H), 7.43-7.35 (m,5H), 7.17 (d, J=8.8 Hz, 2H), 7.09 (d, J=9.2 Hz, 2H), 5.23 (s, 2H),4.32-4.18 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ153.5, 148.1 (d, J=7.5 Hz), 147.7, 134.6, 132.9 (d, J=3.0 Hz), 132.0 (d,J=9.7 Hz), 128.8, 128.7, 128.6, 128.5, 127.4 (d, J=189.8 Hz), 122.1,121.4 (d, J=4.4 Hz), 63.0 (d, J=6.0 Hz), 16.3 (d, J=6.0 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 16.30 ppm.

xlii. 4-(Allyloxy)phenyl ethyl benzylphosphonate (4S)

58.4 mg, 88%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3032, 2981, 2918, 1504, 1454, 1261, 1199, 1037, 933; ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.23 (m, 5H), 7.03-6.97 (m, 2H), 6.85-6.79(m, 2H), 6.08-5.97 (m, 1H), 5.42-5.36 (m, 1H), 5.30-5.25 (m, 1H), 4.48(td, J=5.6, 1.2 Hz, 2H), 4.13-4.00 (m, 2H), 3.23 (dd, J=21.6, 2.8 Hz,2H), 1.19 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.6, 144.1(d, J=8.9 Hz), 133.1, 131.0 (d, J=9.7 Hz), 129.9 (d, J=6.7 Hz), 128.6(d, J=3.7 Hz), 127.0 (d, J=3.7 Hz), 121.3 (d, J=4.5 Hz), 117.7, 115.5,69.2, 63.0 (d, J=7.5 Hz), 33.6 (d, J=137.6 Hz), 16.2 (d, J=6.0 Hz); ³¹PNMR (162 MHz, CDCl₃): δ 24.16 ppm.

xliii. (E)-ethyl (4-(phenyldiazenyl)phenyl) phenylphosphonate (4T)

68.8 mg, 94%; as an orange oil; R_(f) 0.25 (ν_(Hexane)/ν_(EA)=2:1); IR ν(KBr, cm⁻¹) 3059, 2981, 2904, 1593, 1492, 1261, 1226, 1207, 1130, 1037,918; ¹H NMR (400 MHz, CDCl₃) δ 7.94-7.85 (m, 6H), 7.61-7.56 (m, 1H),7.54-7.48 (m, 5H), 7.38-7.29 (m, 2H), 4.37-4.28 (m, 2H), 1.38 (dt,J=6.8, 0.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 152.7 (d, J=7.5 Hz),152.5, 149.5, 133.0 (d, J=3.0 Hz), 132.0 (d, J=9.7 Hz), 131.0, 129.1,128.6 (d, J=5.6 Hz), 127.3 (d, J=189.8 Hz), 124.4, 122.8, 121.1 (d,J=4.5 Hz), 63.1 (d, J=5.9 Hz), 16.3 (d, J=6.6 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 16.21 ppm.

xliv. (E)-ethyl3-(2-((benzyl(ethoxy)phosphoryl)oxy)-5-bromophenyl)acrylate (4U)

73.6 mg, 82%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2981, 2931, 1712, 1635, 1477, 1215, 1273, 1222,1180, 1033, 929; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=16.0 Hz, 1H), 7.67(d, J=0.5 Hz, 1H), 7.37 (dd, J=8.8, 2.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.14(dd, J=8.8, 1.2 Hz, 1H), 6.40 (d, J=16.4 Hz, 1H), 4.28 (q, J=7.2 Hz,1H), 4.15-4.02 (m, 2H), 3.37 (d, J=22.0 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H),1.21 (dt, J=7.2, 0.4 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 166.3, 148.3(d, J=9.6 Hz), 136.9, 133.8, 130.2, 130.1 (d, J=9.7 Hz), 129.9 (d, J=9.4Hz), 128.7 (d, J=3.0 Hz), 127.3 (d, J=3.7 Hz), 122.8 (d, J=2.9 Hz),121.1, 117.9, 63.5 (d, J=6.7 Hz), 60.7, 34.0 (d, J=138.4 Hz), 16.2 (d,J=5.2 Hz), 14.3; ³¹P NMR (162 MHz, CDCl₃): δ 24.71 ppm.

xlv. (3R, 8S, 9S, 10R, 13R, 14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl4-((benzyl(ethoxy)phosphoryl)oxy)benzoate (4V)

115.9 mg, 84%; as a colorless oil; IR ν (KBr, cm⁻¹) 3062, 2939, 286,1712, 1604, 1504, 1458, 1273, 1219, 1161, 1118, 1037, 921; ¹H NMR (400MHz, CDCl₃) δ 7.93 (d, J=8.4 Hz, 2H), 7.35-7.26 (m, 5H), 7.14 (dd,J=8.8, 0.8 Hz, 2H), 5.33-5.29 (m, 1H), 5.22 (t, J=2.4 Hz, 1H), 4.28-4.03(m, 2H), 3.34 (dd, J=21.6, 1.6 Hz, 2H), 2.57 (td, J=15.6, 2.4 Hz, 1H),2.33 (td, J=15.2, 2.4 Hz, 1H), 2.07-1.78 (m, 5H), 1.75-1.68 (m, 1H),1.63-1.00 (m, 23H), 1.22 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 0.86(d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.70 (s, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 165.1, 154.2 (d, J=9.0 Hz), 138.8, 131.4, 130.5 (d, J=8.9Hz), 129.9 (d, J=6.7 Hz), 128.7 (d, J=3.0 Hz), 127.7 (d, J=8.5 Hz),127.2 (d, J=3.7 Hz), 122.4, 120.1 (d, J=4.4 Hz), 71.3, 63.3 (d, J=7.5Hz), 56.7, 56.2, 50.3, 42.3, 39.7, 39.5, 37.1, 36.6, 36.2, 35.8, 34.0,33.9 (d, J=138.4 Hz), 31.9, 31.8, 28.2, 28.0, 26.3, 24.3, 23.8, 22.8,22.5, 20.8, 18.9, 18.7, 16.2 (d, J=6.0 Hz), 11.9; ³¹P NMR (162 MHz,CDCl₃): δ 24.02 ppm;

xlvi. Butyl ethyl phenylphosphonate (5A)

41.1 mg, 81%; as a colorless oil; R_(f) 0.50 (ν_(DCM)/ν_(EA)=95:5); ¹HNMR (400 MHz, CDCl₃) δ 7.86-7.78 (m, 2H), 7.59-7.53 (m, 1H), 7.51-7.44(m, 2H), 4.22-3.96 (m, 4H), 1.71-1.62 (m, 2H), 1.46-1.26 (m, 5H), 0.91(dt, J=7.2, 2.0 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 132.3 (d, J=3.0Hz), 131.7 (d, J=10.4 Hz), 128.4 (d, J=14.9 Hz), 128.3 (d, J=186.8 Hz),65.8 (d, J=5.2 Hz), 62.1 (d, J=5.9 Hz), 32.4 (d, J=6.0 Hz), 18.7, 16.3(d, J=6.7 Hz), 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 19.41 ppm; Spectroscopydata of the this compound matches with the data reported in thecorresponding reference (Ilia et al. (2015) Heteroatom Chemistry 26:29).

xlvii. Ethyl (4-methylcyclohexyl) phenylphosphonate (5B)

41.0 mg, 73%; as a colorless oil; R_(f) 0.25 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2931, 2866, 1454, 1438, 1249, 1130, 1049, 1010, 964; ¹HNMR (400 MHz, CDCl₃) δ 7.85-7.78 (m, 2H), 7.56-7.51 (m, 1H), 7.48-7.42(m, 2H), 4.38-4.27 (m, 1H), 4.17-3.99 (m, 2H), 2.18-2.11 (m, 1H),1.95-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.58-1.28 (m, 6H), 0.86 (d, J=6.4Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 132.1 (d, J=2.9 Hz), 131.7 (d,J=9.7 Hz), 129.3 (d, J=186.8 Hz), 128.3 (d, J=14.8 Hz), 61.8 (d, J=5.2Hz), 33.9 (d, J=3.7 Hz), 33.6 (d, J=4.4 Hz), 33.0 (d, J=5.2 Hz), 31.4,21.7, 16.3 (d, J=6.7 Hz), 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 18.33 ppm.

xlviii. 2-Chloroethyl ethyl phenylphosphonate (5C)

35.8 mg, 72%; as a colorless oil; R_(f) 0.11 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2985, 2908, 1643, 1438, 1238, 1134, 1022, 964; ¹H NMR (400MHz, CDCl₃) δ 7.88-7.79 (m, 2H), 7.61-7.55 (m, 1H), 7.52-7.45 (m, 2H),4.39-4.08 (m, 4H), 3.75-3.64 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 132.7 (d, J=3.0 Hz), 131.8 (d, J=9.7 Hz), 128.5 (d,J=14.9 Hz), 127.5 (d, J=188.3 Hz), 65.2 (d, J=5.2 Hz), 62.5 (d, J=5.2Hz), 42.7 (d, J=7.4 Hz), 16.3 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ19.91 ppm.

xlix. 3-Bromopropyl ethyl phenylphosphonate (5D)

44.2 mg, 72%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=1:1); IRν (KBr, cm⁻¹) 2978, 2904, 1643, 1438, 1242, 1130, 1014, 964; ¹H NMR (400MHz, CDCl₃) δ 7.81 (dd, J=13.2, 7.2 Hz, 2H), 7.58 (t, J=7.2 Hz, 1H),7.52-7.45 (m, 2H), 4.27-4.05 (m, 4H), 3.53-3.46 (m, 2H), 2.24-2.15 (m,2H), 1.34 (t, J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 132.6 (d,J=3.0 Hz), 131.8 (d, J=9.7 Hz), 128.5 (d, J=14.9 Hz), 127.8 (d, J=184.6Hz), 63.5 (d, J=6.0 Hz), 62.3 (d, J=6.0 Hz), 33.3 (d, J=6.7 Hz), 29.1,16.3 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 19.74 ppm.

l. Isopropyl methyl phenylphosphonate (5E)

31.5 mg, 74%; as a colorless oil; R_(f) 0.10 (ν_(Hexane)/ν_(EA)=1:1); IRν (KBr, cm⁻¹) 3059, 2978, 2951, 1438, 1377, 1253, 1134, 1045, 991; ¹HNMR (400 MHz, CDCl₃) δ 7.86-7.78 (m, 2H), 7.59-7.52 (m, 1H), 7.50-7.43(m, 2H), 4.81-4.68 (m, 1H), 3.73 (dd, J=11.2, 2.4 Hz, 3H), 1.40 (dd,J=6.4, 1.6 Hz, 2H), 1.27 (dd, J=6.0, 1.6 Hz, 3H); ¹³C NMR (100.5 MHz,CDCl₃) δ 132.3 (d, J=3.0 Hz), 131.7 (d, J=9.7 Hz), 128.4 (d, J=188.3Hz), 128.3 (d, J=14.9 Hz), 71.1 (d, J=6.0 Hz), 52.3 (d, J=5.9 Hz), 24.0(d, J=3.7 Hz), 23.8 (d, J=4.5 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 19.75ppm.

li. Benzyl ethyl phenylphosphonate (5F)

34.8 mg, 63%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.85-7.78 (m, 2H), 7.57-7.52 (m, 1H), 7.48-7.42(m, 2H), 7.37-7.27 (m, 5H), 5.17-5.49 (m, 2H), 4.19-4.04 (m, 2H), 1.30(dt, J=7.2, 0.4 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 136.2 (d, J=6.7Hz), 132.5 (d, J=3.0 Hz), 131.8 (d, J=9.7 Hz), 128.5, 128.4 (d, J=14.9Hz), 128.3, 128.0 (d, J=188.2 Hz), 127.8, 67.4 (d, J=5.2 Hz), 62.3 (d,J=5.2 Hz), 16.3 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 19.82 ppm;Spectroscopy data of the this compound matches with the data reported inthe corresponding reference (Xu et al. (2014) Adv. Synth. Catal. 356:3331).

lii. Ethyl (3-phenylpropyl) phenylphosphonate (5G)

43.1 mg, 71%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=1:1); IRν (KBr, cm⁻¹) 3028, 2981, 2958, 1643, 1438, 1246, 1130, 1018, 968; ¹HNMR (400 MHz, CDCl₃) δ 7.86-7.78 (m, 2H), 7.58-7.53 (m, 1H), 7.50-7.44(m, 2H), 7.26 (t, J=7.6 Hz, 5H), 7.20-7.12 (m, 3H), 4.21-3.98 (m, 4H),2.70 (t, J=7.6 Hz, 2H), 2.03-1.95 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 141.0, 132.4 (d, J=3.0 Hz), 131.8 (d, J=9.7Hz), 128.5, 128.4, 128.3, 128.27 (d, J=187.5 Hz), 126.0, 65.2 (d, J=5.2Hz), 62.1 (d, J=5.2 Hz), 32.0 (d, J=6.7 Hz), 31.7, 16.3 (d, J=6.7 Hz);³¹P NMR (162 MHz, CDCl₃): δ 19.49 ppm.

liii. 2,2-Diphenylethyl ethyl phenylphosphonate (5H)

59.3 mg, 81%; as a colorless oil; R_(f) 0.36 (ν_(Hexane)/ν_(EA)=1:1); IRν (KBr, cm⁻¹) 3028, 2981, 2900, 1492, 1438, 1249, 1130, 1014, 964; ¹HNMR (400 MHz, CDCl₃) δ 7.68-7.59 (m, 2H), 7.50 (dt, J=7.2, 1.6 Hz, 1H),7.41-7.34 (m, 2H), 7.31-7.17 (m, 10H), 4.66-4.59 (m, 1H), 4.53-4.45 (m,1H), 4.37 (t, J=7.2 Hz, 1H), 4.00-3.92 (m, 2H), 1.22 (t, J=6.8 Hz, 3H);¹³C NMR (100.5 MHz, CDCl₃) δ 140.7 (d, J=1.5 Hz), 132.2 (d, J=3.0 Hz),131.7 (d, J=9.7 Hz), 128.5, 128.4, 128.3 (d, J=2.2 Hz), 128.0 (d,J=188.3 Hz), 126.0, 68.0 (d, J=5.9 Hz), 62.1 (d, J=5.2 Hz), 51.4 (d,J=7.4 Hz), 16.2 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 19.31 ppm.

liv. Ethyl (4-methyl-2-oxo-2H-chromen-7-yl) phenylphosphonate (6A)

49.5 mg, 72%; as a colorless oil; R_(f) 0.25 (ν_(DCM)/ν_(EA)=9:1); IR ν(KBr, cm⁻¹) 3062, 2985, 1728, 1570, 1489, 1431, 1257, 1161, 1130, 1037,960; ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.85 (m, 2H), 7.61 (dt, J=7.6, 1.6Hz, 1H), 7.54-7.47 (m, 2H), 7.40 (t, J=2.4 Hz, 1H), 7.32-7.22 (m, 2H),6.30 (d, J=0.8 Hz, 1H), 4.35-4.20 (m, 2H), 2.36 (d, J=1.2 Hz, 3H), 1.38(t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 160.4, 151.7, 150.3,146.5 (d, J=7.5 Hz), 133.1 (d, J=3.8 Hz), 132.0 (d, J=10.4 Hz), 128.7(d, J=15.6 Hz), 127.0 (d, J=189.8 Hz), 124.3 (d, J=4.5 Hz), 120.6,118.2, 116.1 (d, J=4.5 Hz), 115.7, 63.2 (d, J=6.0 Hz), 18.6, 16.3 (d,J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 16.96 ppm.

lv. (E)-ethyl3-(4-((ethoxy(phenyl)phosphoryl)oxy)-3-methoxyphenyl)acrylate (6B)

67.8 mg, 87%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 2981, 2935, 1708, 1635, 1508, 1261, 1157, 1130,1033, 914; ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.88 (m, 2H), 7.62-7.54 (m,2H), 7.51-7.44 (m, 2H), 7.24 (dd, J=8.8, 1.2 Hz, 1H), 7.05-7.01 (m, 2H),6.33 (d, J=16.4 Hz, 1H), 4.35-4.22 (m, 4H), 3.77 (s, 3H), 1.38 (t, J=6.8Hz, 3H), 1.33 (dt, J=7.2, 0.4 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ166.8, 151.0 (d, J=4.5 Hz), 143.8, 141.4 (d, J=7.5 Hz), 132.7 (d, J=3.0Hz), 132.0, 131.9 (d, J=10.4 Hz), 128.3 (d, J=15.6 Hz), 127.8 (d,J=191.3 Hz), 122.0 (d, J=3.7 Hz), 121.3 (d, J=1.5 Hz), 118.0, 111.4,62.9 (d, J=5.9 Hz), 60.5, 55.7, 16.3 (d, J=6.7 Hz), 14.3; ³¹P NMR (162MHz, CDCl₃): δ 16.62 ppm;

lvi. Ethyl ((8R, 9S, 13S, 14S,17S)-17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[A]phenanthren-3-yl)benzylphosphonate (6C)

37.1 mg, 41%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=1:1); IRν (KBr, cm⁻¹) 3421, 2032, 2927, 2866, 1643, 1608, 1492, 1226, 1037, 968;¹H NMR (400 MHz, CDCl₃) δ 7.35-7.24 (m, 5H), 7.18 (d, J=8.4 Hz, 1H),6.84 (d, J=8.8 Hz, 2H), 6.78 (s, 1H), 4.15-4.03 (m, 2H), 2.34-1.18 (m,16H), 0.77 (s, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.3 (d, J=8.9 Hz),138.4, 136.9, 131.1 (d, J=9.6 Hz), 129.9 (d, J=7.4 Hz), 128.5 (d, J=3.0Hz), 127.0 (d, J=3.0 Hz), 120.4 (d, J=2.9 Hz), 117.5 (d, J=3.7 Hz), 62.9(d, J=7.4 Hz), 50.0, 44.0, 43.2, 38.5, 36.6, 33.7 (d, J=138.4 Hz), 30.5,29.5, 27.0, 26.2, 23.1, 16.2 (d, J=5.9 Hz), 11.0; ³¹P NMR (162 MHz,CDCl₃): δ 23.87 ppm.

lvii. Benzo [D][1,3]dioxol-5-yl ethyl benzylphosphonate (6D)

57.6 mg, 90%; as a colorless oil; R_(f) 0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3062, 2981, 2904, 1631, 1608, 1481, 1246, 1172, 1126,1033, 956; ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.25 (m, 5H), 6.68 (d, J=8.4Hz, 1H), 6.60 (dd, J=2.4, 1.2 Hz, 1H), 6.54-6.57 (m, 1H), 5.94 (s, 2H),4.14-4.00 (m, 2H), 3.29 (dd, J=21.2, 2.4 Hz, 3H), 1.20 (dt, J=7.2, 0.8Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.0, 144.8 (d, J=8.9 Hz), 144.6,130.9 (d, J=9.7 Hz), 129.9 (d, J=6.7 Hz), 128.6 (d, J=3.0 Hz), 127.1 (d,J=3.7 Hz), 112.8 (d, J=3.7 Hz), 107.9 (d, J=1.5 Hz), 102.9 (d, J=3.7Hz), 101.6, 63.1 (d, J=6.7 Hz), 33.6 (d, J=138.4 Hz), 16.2 (d, J=5.9Hz); ³¹P NMR (162 MHz, CDCl₃): δ 24.28 ppm.

lviii. Ethyl (2-methyl-4-oxo-4H-pyran-3-yl) phenylphosphonate (6E)

30.0 mg, 51%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=1:1); IRν (KBr, cm⁻¹) 3078, 2927, 2854, 1654, 1438, 1249, 1180, 1033; ¹H NMR(400 MHz, CDCl₃) δ 8.02-7.95 (m, 2H), 7.61 (d, J=6.0 Hz, 1H), 7.58 (dd,J=7.6, 2.0 Hz, 1H), 7.53-7.46 (m, 2H), 6.36 (d, J=5.6 Hz, 1H), 4.47-4.32(m, 2H), 2.26 (d, J=1.6 Hz, 3H), 1.38 (t, J=6.8 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 172.7, 159.0 (d, J=5.2 Hz), 153.7, 139.1 (d, J=8.9 Hz),132.7 (d, J=3.7 Hz), 131.8 (d, J=9.7 Hz), 128.4 (d, J=15.7 Hz), 128.1(d, J=194.3 Hz), 116.8, 63.5 (d, J=5.9 Hz), 16.3 (d, J=6.7 Hz), 15.7;³¹P NMR (162 MHz, CDCl₃): δ 17.50 ppm.

lix. Ethyl (((S)-4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl)phenylphosphonate (6F)

44.8 mg, 70%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2978, 2927, 2839, 1643, 1438, 1234, 1130, 1022, 983; ¹HNMR (400 MHz, CDCl₃) δ 7.85-7.78 (m, 2H), 7.58-7.52 (m, 1H), 7.49-7.43(m, 2H), 5.75 (s, 1H), 4.73-4.67 (m, 2H), 4.50-4.35 (m, 2H), 4.21-4.14(m, 2H), 2.13-1.75 (m, 7H), 1.71 (t, J=0.8 Hz, 3H), 1.33 (dt, J=6.8, 0.4Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 149.5, 133.0, 132.9 (d, J=5.9 Hz),132.3 (dd, J=3.0, 1.5 Hz), 131.8 (dd, J=9.7, 2.3 Hz), 128.5 (d, J=187.6Hz), 128.4 (d, J=14.9 Hz), 126.2 (d, J=10.4 Hz), 69.9 (dd, J=5.2, 3.7Hz), 62.1 (d, J=4.4 Hz), 40.7 (d, J=5.2 Hz), 30.4, 27.1 (d, J=2.2 Hz),26.0 (d, J=5.2 Hz), 24.7, 20.7 (d, J=3.7 Hz), 16.3 (d, J=6.7 Hz); ³¹PNMR (162 MHz, CDCl₃): δ 19.62 ppm.

lx. (3S, 8S, 9S, 10R, 13R, 14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ylethyl phenylphosphonate (6G)

89.8 mg, 81%; as a white solid; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃, * denotes minor rotamer peaks) δ 7.86-7.78 (m, 2H),7.56-7.51 (m, 1H), 7.49-7.42 (m, 2H), 5.38* (d, J=4.8 Hz, 1H), 5.27 (d,J=5.2 Hz, 1H), 4.33-4.21 (m, 1H), 4.18-4.00 (m, 2H), 2.49 (d, J=8.0 Hz,1H), 2.45-2.36 (m, 1H), 2.30-2.23* (m, 1H), 2.08-0.94 (m, 32H), 0.91 (d,J=6.4 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.66 (s,3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 139.5, 139.4, 132.2 (d, J=1.5 Hz),132.1 (d, J=1.5 Hz), 131.7 (d, J=9.6 Hz), 129.2 (d, J=188.3 Hz), 129.1(d, J=186.8 Hz), 128.4 (d, J=14.9 Hz), 128.3 (d, J=14.9 Hz), 122.8,1227, 76.8 (d, J=6.0 Hz), 76.7 (d, J=6.0 Hz), 61.9, 61.8, 56.6, 56.1,49.9, 42.3, 40.3 (d, J=3.7 Hz), 40.1 (d, J=5.2 Hz), 39.7, 39.5, 36.92,36.89, 36.4, 36.1, 35.7, 31.9, 31.8, 31.79, 31.78, 30.0 (d, J=3.0 Hz),29.8 (d, J=3.7 Hz), 28.2, 28.0, 24.2, 23.8, 22.8, 22.5, 21.0, 19.2,18.7, 16.3 (d, J=6.7 Hz), 11.8; ³¹P NMR (162 MHz, CDCl₃): δ 18.29 ppm;Spectroscopy data of the this compound matches with the data reported inthe corresponding reference (Kalek et al. (2008) Org. Lett. 10: 4637).

lxi. 2-Cyanophenyl ethyl benzylphosphonate (7A)

Methyl naphthalen-1-yl (4-methylpent-3-en-1-yl)phosphonate (7b): 54.8mg, 91%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); ¹H NMR(400 MHz, CDCl₃) δ 7.61-7.57 (m, 1H), 7.50-7.44 (m, 1H), 7.39-7.24 (m,6H), 7.19 (tt, J=7.6, 0.8 Hz, 1H), 4.24-4.11 (m, 2H), 3.44 (d, J=22.0Hz, 2H), 1.25 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 152.4 (d,J=8.2 Hz), 134.3, 133.4, 130.0 (d, J=6.7 Hz), 129.9 (d, J=9.6 Hz), 128.7(d, J=3.0 Hz), 127.3 (d, J=3.7 Hz), 124.8, 121.1 (d, J=2.3 Hz), 115.5,105.5 (d, J=6.0 Hz), 63.7 (d, J=7.4 Hz), 34.1 (d, J=137.7 Hz), 16.2 (d,J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 25.03 ppm; Spectroscopy data ofthe this compound matches with the data reported in the correspondingreference (Bera et al. (2016) ACS Catal. 6: 3575).

lxii. Methyl naphthalen-1-yl (4-methylpent-3-en-1-yl)phosphonate (7B)

51.0 mg, 84%; as a colorless oil; R_(f) 0.15 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 8.17-8.12 (m, 1H), 7.87-7.82 (m, 1H), 7.66 (d,J=8.0 Hz, 1H), 7.56-7.49 (m, 3H), 7.41 (t, J=8.4 Hz, 1H), 5.13 (t, J=7.2Hz, 2H), 7.80 (dd, J=11.2, 0.8 Hz, 3H), 2.47-2.36 (m, 2H), 2.07-1.98 (m,2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.33 (t, J=7.6 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 146.5, 134.8, 133.3 (d, J=8.5 Hz), 127.8, 126.6, 126.5,126.3, 125.6 (d, J=1.5 Hz), 124.6 (d, J=1.4 Hz), 122.7 (d, J=17.2 Hz),121.6, 115.3 (d, J=3.0 Hz), 52.9 (d, J=7.4 Hz), 25.8 (d, J=137.7 Hz),25.6, 21.1 (d, J=4.5 Hz), 17.6; ³¹P NMR (162 MHz, CDCl₃): δ 31.17 ppm;Spectroscopy data of the this compound matches with the data reported inthe corresponding reference (Foust et al. (2017) ACS Med. Chem. Lett. 8:914).

lxiii. Ethyl (4-nitrophenyl) hex-5-en-1-ylphosphonate (7B)

54.5 mg, 87%; as a colorless oil; R_(f) 0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2935, 2866, 1593, 1523, 1492, 1346, 1226, 1037, 910;¹H NMR (400 MHz, CDCl₃) δ 8.24 (td, J=9.2, 3.2 Hz, 2H), 7.42-7.36 (m,2H), 5.84-5.72 (m, 1H), 5.05-4.95 (m, 2H), 4.30-4.10 (m, 2H), 2.13-2.05(m, 2H), 2.00-1.90 (m, 2H), 1.76-1.67 (m, 2H), 1.57-1.48 (m, 2H), 1.33(t, J=7.6 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.7 (d, J=8.9 Hz),144.5, 137.8, 125.6, 120.9 (d, J=4.5 Hz), 115.1, 62.9 (d, J=7.5 Hz),33.0 (d, J=1.5 Hz), 29.5 (d, J=7.2 Hz), 25.9 (d, J=139.2 Hz), 21.6 (d,J=5.2 Hz), 16.3 (d, J=5.2 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 30.84 ppm.

lxiv. O-ethyl S-phenyl phenylphosphonothioate (8A)

8.1 mg, 14%; as a colorless oil; R₁ 0.20 (ν_(Hexane)/ν_(EA)=2:1); IR ν(KBr, cm⁻¹) 3059, 2981, 2924, 1643, 1438, 1230, 1118, 1022, 956; ¹H NMR(400 MHz, CDCl₃) δ 7.69-7.62 (m, 2H), 7.53-7.47 (m, 1H), 7.40-7.34 (m,2H), 7.32-7.26 (m, 3H), 7.21 (t, J=7.2 Hz, 2H), 4.43-4.27 (m, 2H), 1.41(t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 135.5 (d, J=4.4 Hz),132.4 (d, J=3.7 Hz), 131.5 (d, J=149.6 Hz), 131.4 (d, J=10.5 Hz), 129.1(d, J=2.2 Hz), 128.9 (d, J=3.0 Hz), 128.2 (d, J=14.9 Hz), 126.6 (d,J=5.2 Hz), 62.4 (d, J=7.4 Hz), 16.3 (d, J=6.7 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 42.26 ppm.

c. General Procedure for the Synthesis of Phosphate Derivatives

Diethyl phenyl phosphate (3a′): To a solution of triethyl phosphate 1a(36.4 mg, 0.2 mmol), Tf₂O (50.5 μL, 0.3 mmol) in DCM (1.0 mL) was addedpyridine (32 μL, 0.4 mmol) in a 2-dram vial with a PTFE cap. Afterstirring for 10 min, phenol (38.1 mg, 0.4 mmol) was added to thereaction mixture. After stirring for another 30 min at room temperature,the resulting mixture was concentrated to give the crude product whichwas then purified by column chromatography on silica gel (PE/EA=3:1) toafford ethyl phenyl benzylphosphonate (3a′).

i. Ethyl phenyl benzylphosphonate (3A′)

42.3 mg, 92%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.37-7.30 (m, 2H), 7.24-7.20 (m, 2H), 7.19-7.14(m, 1H), 4.28-4.15 (m, 4H), 1.35 (td, J=7.2, 1.2 Hz, 6H); ¹³C NMR (100.5MHz, CDCl₃) δ 150.8, 129.6, 124.9, 119.9 (d, J=4.4 Hz), 64.5 (d, J=5.9Hz), 16.0 (d, J=6.7 Hz); Spectroscopy data of the compound match withthe data reported in the corresponding reference (Panmand et al. (2014)Tetrahedron Lett. 55: 5898-5901).

ii. Diethyl p-tolyl phosphate (3B′)

43.9 mg, 90%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.15-7.07 (m, 4H), 4.27-4.14 (m, 4H), 2.32 (s,3H), 1.38-1.32 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.5 (d, J=6.7Hz), 134.5, 130.1, 119.7 (d, J=4.5 Hz), 64.4 (d, J=5.9 Hz), 20.7, 16.1(d, J=6.7 Hz); Spectroscopy data of the compound match with the datareported in the corresponding reference (Jeon et al. (2013) Tetrahedron69: 5152-5159).

iii. Diethyl (4-methoxyphenyl) phosphate (3c′)

46.3 mg, 89%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.17-7.11 (m, 2H), 6.84 (d, J=8.8 Hz, 2H),4.27-4.13 (m, 4H), 3.78 (s, 3H), 1.37-1.33 (m, 6H); ¹³C NMR (100.5 MHz,CDCl₃) δ 156.6 (d, J=1.5 Hz), 144.3, 120.8 (d, J=5.4 Hz), 114.6, 64.5(d, J=5.9 Hz), 55.6, 16.1 (d, J=6.7 Hz); Spectroscopy data of thecompound match with the data reported in the corresponding reference(Jones and Smanmoo (2005) Org. Lett. 7: 3271-3274).

iv. 4-Bromophenyl diethyl Phosphate (3D′)

52.4 mg, 85%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.14-7.10 (m, 2H), 4.27-4.15(m, 4H), 1.35 (td, J=6.8, 1.2 Hz, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ149.8 (d, J=6.7 Hz), 132.6, 121.8 (d, J=5.2 Hz), 117.8, 64.7 (d, J=6.0Hz), 16.0 (d, J=6.7 Hz); Spectroscopy data of the compound match withthe data reported in the corresponding reference (Jones and Smanmoo(2005) Org. Lett. 7: 3271-3274).

v. Diethyl (4-iodophenyl) phosphate (3E′)

61.9 mg, 87%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.67-7.62 (m, 2H), 7.03-6.97 (m, 2H), 4.28-4.16(m, 4H), 1.39-1.32 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.7 (d, J=7.4Hz), 138.7, 122.2 (d, J=5.2 Hz), 88.5, 64.7 (d, J=5.9 Hz), 16.1 (d,J=6.7 Hz); Spectroscopy data of the compound match with the datareported in the corresponding reference (Wang et al. (2014) Chem. Sci.5: 3952-3957).

vi. Diethyl (4-nitrophenyl) phosphate (3F′)

46.7 mg, 85%; as a colorless oil; R_(f)=0.15 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 8.28-8.22 (m, 2H), 7.43-7.37 (m, 2H), 4.33-4.21(m, 4H), 1.42-1.36 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.5 (d, J=6.7Hz), 144.6, 125.6, 120.5 (d, J=5.2 Hz), 65.1 (d, J=5.9 Hz), 16.0 (d,J=5.9 Hz); Spectroscopy data of the compound match with the datareported in the corresponding reference (Jones and Smanmoo (2005) Org.Lett. 7: 3271-3274).

vii. Diethyl o-tolyl phosphate (3G′)

34.6 mg, 71%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.29 (d, J=8.0 Hz, 1H), 7.21-7.13 (m, 2H), 7.06(t, J=7.2 Hz, 1H), 4.29-4.15 (m, 4H), 2.32 (s, 3H), 1.38-1.33 (m, 6H);¹³C NMR (100.5 MHz, CDCl₃) δ 149.2, 131.3, 129.2 (d, J=6.7 Hz), 126.9,124.9, 119.7 (d, J=3.0 Hz), 64.5 (d, J=5.9 Hz), 16.3, 16.1 (d, J=6.7Hz); Spectroscopy data of the compound match with the data reported inthe corresponding reference (Jeon et al. (2013) Tetrahedron 69:5152-5159).

viii. Diethyl m-tolyl phosphate (3H′)

44.4 mg, 91%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.21 (t, J=7.6 Hz, 1H), 7.06-6.96 (m, 3H),4.28-4.15 (m, 4H), 2.35 (s, 3H), 1.39-1.33 (m, 6H); ¹³C NMR (100.5 MHz,CDCl₃) δ 150.7 (d, J=6.6 Hz), 139.9, 129.3, 125.7, 120.5 (d, J=5.2 Hz),116.8 (d, J=4.4 Hz), 64.5 (d, J=5.9 Hz), 21.3, 16.0 (d, J=6.7 Hz);Spectroscopy data of the compound match with the data reported in thecorresponding reference (Jeon et al. (2013) Tetrahedron 69: 5152-5159).

ix. [1,1′-biphenyl]-4-yl diethyl phosphate (3I ′)

52.0 mg, 85%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 2985, 2908, 1604, 1516, 1485, 1280, 1222, 1165,1099, 1033, 960; ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m, 4H), 7.46-7.40(m, 2H), 7.37-7.25 (m, 3H), 4.30-4.20 (m, 4H), 1.37 (td, J=7.2, 0.8 Hz,6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.2 (d, J=6.7 Hz), 140.2, 138.1,128.8, 128.4, 127.3, 127.0, 120.2 (q, J=5.2 Hz), 64.6 (d, J=5.9 Hz),16.1 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ−5.63 ppm; HRMS (ESI):m/z calcd. for C₁₆H₁₉O₄P ([M+H]⁺): 307.1094; Found: 307.1092.

x. Diethyl naphthalen-1-yl phosphate (3J′)

46.4 mg, 82%; as a colorless oil; R_(f)=0.25 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3059, 2985, 2908, 1597, 1508, 1462, 1392, 1280, 1234,1037, 964; ¹H NMR (400 MHz, CDCl₃) δ 8.20-8.16 (m, 1H), 7.87-7.82 (m,1H), 7.66 (d, J=8.0 Hz, 1H), 7.57-7.48 (m, 3H), 7.41 (dt, J=8.0, 1.2Hz), 4.33-4.18 (m, 4H), 1.38-1.31 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ146.6 (d, J=7.4 Hz), 134.7, 127.7, 126.6, 126.4 (d, J=6.7 Hz), 126.3,125.5 (d, J=1.5 HZ), 124.8 (q, J=8.5 Hz), 121.6, 114.8 (d, J=3.0 Hz),64.7 (d, J=5.9 Hz), 16.1 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ−5.44 ppm; HRMS (ESI): m/z calcd. for C₁₄H₁₇O₄P ([M+H]⁺): 281.0937;Found: 281.0927.

xi. Diethyl naphthalen-2-yl phosphate (3K′)

43.6 mg, 78%; as a colorless oil; R_(f)=0.25 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.81 (t, J=9.2 Hz, 3H), 7.69 (d, J=1.2 Hz, 1H),7.51-7.41 (m, 2H), 7.39-7.34 (m, 1H), 4.32-4.18 (m, 4H), 1.39-1.33 (m,6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.3 (d, J=7.5 Hz), 133.9, 130.9,129.8, 127.7, 127.5, 126.7, 125.4, 120.0 (d, J=5.2 Hz), 116.3 (d, J=4.5Hz), 64.7 (d, J=6.0 Hz), 16.1 (d, J=6.7 Hz); Spectroscopy data of thecompound match with the data reported in the corresponding reference(Panmand et al. (2014) Tetrahedron Lett. 55: 5898-5901).

xii. 2,6-Dimethylphenyl diethyl phosphate (3L′)

41.3 mg, 80%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)Iν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.04-6.94 (m, 3H), 4.27-4.13 (m, 4H), 2.37 (s,6H), 1.37-1.31 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.1 (d, J=8.1Hz), 130.3 (d, J=3.8 Hz), 128.9 (d, J=1.5 Hz), 125.0 (d, J=2.2 Hz), 64.4(d, J=5.9 Hz), 17.1, 16.1 (d, J=6.7 Hz); Spectroscopy data of thecompound match with the data reported in the corresponding reference(You et al. (2013) Org. Lett. 15: 1610-1613).

xiii. 2,6-Diisopropylphenyl diethyl phosphate (3M′)

33.4 mg, 53%; as a colorless oil; R_(f)=0.50 (ν_(Hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.15-7.10 (m, 3H), 4.27-4.11 (m, 4H), 3.56-3.45(m, 2H), 1.36-1.30 (m, 6H), 1.22 (dd, J=6.8, 1.2 Hz, 12H); ¹³C NMR(100.5 MHz, CDCl₃) δ 145.5, 140.6 (d, J=2.9 Hz), 125.6 (d, J=2.3 Hz),124.1 (d, J=1.4 Hz), 64.3 (d, J=5.9 Hz), 26.8, 23.5, 16.1 (d, J=6.7 Hz);Spectroscopy data of the compound match with the data reported in thecorresponding reference (Guzmin and Diaz (1997) Syn. Commun. 27:3035-3038).

xiv. Diisopropyl phenyl phosphate (3N′)

37.7 mg, 73%; as a colorless oil; R_(f)=0.30 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2935, 1593, 1492, 1384, 1276, 1215, 1107, 1010, 941;¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.25-7.20 (m, 2H),7.18-7.12 (m, 1H), 4.81-4.69 (m, 4H), 1.36 (d, J=6.0 Hz, 3H), 1.31 (d,J=6.0 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 151.0, 129.5, 124.7, 120.0(d, J=5.3 Hz), 73.4 (d, J=6.7 Hz), 23.6 (d, J=5.2 Hz), 23.5 (d, J=5.2Hz); ³¹P NMR (162 MHz, CDCl₃): δ −7.42 ppm; HRMS (ESI): m/z calcd. forC₁₂H₁₉O₄P ([M+H]⁺): 259.1094; Found: 259.1091.

xv. Benzyl (4-((diethoxyphosphoryl)Oxy)phenyl) carbonate (3O′)

63.8 mg, 84%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3066, 2985, 2912, 1762, 1500, 1265, 1195, 1053, 1029, 960;¹H NMR (400 MHz, CDCl₃) δ 7.46-7.35 (m, 5H), 7.26-7.20 (m, 2H),7.18-7.13 (m, 2H), 5.27 (s, 2H), 4.28-4.14 (m, 4H), 1.38-1.32 (m, 6H);¹³C NMR (100.5 MHz, CDCl₃) δ 153.5, 148.3 (d, J=6.7 Hz), 147.8 (d, J=8.5Hz), 134.6, 128.7 (d, J=11.1 Hz), 128.5, 122.1, 120.8 (d, J=5.2 Hz),70.4, 64.7 (d, J=6.0 Hz), 16.1, 16.0 (d, J=6.7 Hz); ³¹P NMR (162 MHz,CDCl₃): δ −5.77 ppm; HRMS (ESI): m/z calcd. for C₁₈H₂₁O₇P ([M+H]⁺):381.1098; Found: 381.1093.

xvi. Diethyl (4-methyl-2-oxo-2H-chromen-7-yl) phosphate (3P′)

55.5 mg, 89%; as a colorless oil; R_(f)=0.20 (ν_(DCM)/ν_(EA)=5:1); ¹HNMR (400 MHz, CDCl₃) δ 7.48 (d, J=1.2 Hz, 1H), 7.42-7.38 (m, 1H), 7.31(d, J=8.8 Hz, 1H), 6.33 (d, J=0.8 Hz, 3H), 4.32-4.18 (m, 4H), 2.44 (d,J=1.2 Hz, 3H), 1.38 (td, J=6.8, 1.2 Hz, 6H); ¹³C NMR (100.5 MHz, CDCl₃)δ 160.3, 151.6, 150.4, 146.8 (d, J=6.7 Hz), 123.7 (d, J=4.5 Hz), 120.7,118.2, 115.8, 115.4 (d, J=5.2 Hz), 64.8 (d, J=5.9 Hz), 18.6, 16.1 (d,J=6.0 Hz); Spectroscopy data of the compound match with the datareported in the corresponding reference (Jeon et al. (2013) Tetrahedron69: 5152-5159).

xvii. Benzo [d][1,3]dioxol-5-yl diethyl phosphate (3Q′)

49.8 mg, 91%; as a colorless oil; R_(f)=0.10 (ν_(hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 6.77-6.65 (m, 3H), 5.96 (s, 2H), 4.26-4.16 (m,4H), 1.40-1.32 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 148.0, 145.1 (d,J=6.7 Hz), 144.7, 112.3 (d, J=5.2 Hz), 108.0, 102.5 (d, J=4.5 Hz),101.6, 64.5 (d, J=5.9 Hz), 16.1 (d, J=6.7 Hz); Spectroscopy data of thecompound match with the data reported in the corresponding reference(Lazzaroni et al. (2009) Org. Lett. 11: 349-352).

xviii. (E)-Ethyl 3-(4-((diethoxyphosphoryl)oxy)-3-methoxyphenyl)acrylate(3R′)

60.1 mg, 84%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2981, 2939, 1708, 1635, 1589, 1512, 1265, 1176, 1161,1033, 960; ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=16.0 Hz, 1H), 7.31 (d,J=8.8 Hz, 1H), 7.09 (s, 1H), 7.08 (d, J=6.4 Hz, 1H), 6.37 (d, J=16.0 Hz,1H), 4.31-4.20 (m, 6H), 3.90 (s, 3H), 1.40-1.22 (m, 9H); ¹³C NMR (100.5MHz, CDCl₃) δ 166.8, 150.9 (d, J=6.0 Hz), 143.7, 141.5 (d, J=6.7 Hz),132.1 (d, J=1.5 Hz), 121.5 (d, J=3.0 Hz), 121.3, 118.2, 111.4, 64.6 (d,J=6.0 Hz), 60.5, 55.9, 16.0 (d, J=6.7 Hz), 14.3; ³¹P NMR (162 MHz,CDCl₃): δ −5.63 ppm; HRMS (ESI): m/z calcd. for C₁₆H₂₃O₇P ([M+H]⁺):359.1254; Found: 359.1255.

xix. (3R, 8S, 9R, 10S, 13R, 14R)-8, 9, 10, 13,14-pentamethyl-17-((R)-6-methylheptan-2-yl)-2, 3, 4, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[A]phenanthren-3-yl4-((diethoxyphosphoryl)oxy)benzoate (3S′)

97.6 mg, 76%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 2939, 2866, 1716, 1604, 1504, 1465, 1276, 1226, 1056,1029, 960; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (dd, J=8.8, 1.2 Hz, 2H),7.30-7.24 (m, 2H), 5.33-5.29 (m, 1H), 5.23 (s, 1H), 4.30-4.18 (m, 4H),2.57 (d, J=15.2 Hz, 1H), 2.33 (d, J=15.2 Hz, 1H), 2.07-1.80 (m, 5H),1.72 (d, J=14.0 Hz, 1H), 1.63-1.01 (m, 29H), 0.93 (d, J=5.6 Hz, 3H),0.87 (dd, J=6.8, 2.0 Hz, 6H), 0.70 (s, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ165.1, 154.2 (d, J=6.7 Hz), 138.3, 131.4, 127.8, 122.4, 119.7 (d, J=5.2Hz), 71.3, 64.7 (d, J=6.7 Hz), 56.7, 56.2, 50.3, 42.3, 39.7, 39.5, 37.1,36.6, 36.2, 35.8, 34.0, 31.9, 31.8, 28.2, 28.0, 26.3, 24.2, 23.8, 22.8,22.5, 20.8, 18.9, 18.7, 16.0 (d, J=6.7 Hz), 11.8; ³¹P NMR (162 MHz,CDCl₃): δ −6.21 ppm; HRMS (ESI): m/z calcd. for C₃₈H₅₉O₆P ([M+H]⁺):643.4122; Found: 643.4120.

xx. Diethyl (3-phenylpropyl) phosphate (3T′)

47.3 mg, 87%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=2:1); IRν (KBr, cm⁻¹) 3028, 2981, 1604, 1496, 1454, 1392, 1273, 1165, 1029, 975;¹H NMR (400 MHz, CDCl₃) δ 7.32-7.26 (m, 2H), 7.23-7.17 (m, 3H),4.16-4.02 (m, 6H), 2.73 (t, J=7.6 Hz, 2H), 2.05-1.96 (m, 2H), 1.37-1.32(m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 141.0, 128.4, 126.0, 66.7 (d,J=5.9 Hz), 63.7 (d, J=6.0 Hz), 31.9 (d, J=6.7 Hz), 31.6, 16.1 (d, J=6.7Hz); ³¹P NMR (162 MHz, CDCl₃): δ −0.28 ppm; HRMS (ESI): m/z calcd. forC₁₃H₂₁O₄P ([M+H]⁺): 273.1250; Found: 273.1258.

xxi. Diethyl isopropyl phosphate (3U′)

26.1 mg, 65%, as a colorless oil; R_(f)=0.3 (ν_(EA)/ν_(Hexane)=9:1); ¹HNMR (400 MHz, CDCl₃) δ 4.67-4.62 (1H, m), 4.14-4.06 (4H, m), 1.36-1.32(12H, m); ¹³C NMR (100.5 MHz, CDCl₃), δ 72.3 (d, J=6.0 Hz), 63.4 (d,J=6.0 Hz), 23.4 (d, J=5.1 Hz), 16.1 (d, J=6.2 Hz); Spectroscopy data ofthe compound match with the data reported in the corresponding reference(Jones and Smanmoo (2005) Org. Lett. 7: 3271-3274).

xxii. Cyclohexyl diethyl phosphate (3V′)

23.1 mg, 49%, as a colorless oil; R_(f)=0.3 (ν_(EA)/ν_(Hexane)=9:1); ¹HNMR (400 MHz, CDCl₃) δ 4.38-4.35 (1H, m), 4.14-4.06 (4H, m), 1.96-1.93(2H, m), 1.77-1.74 (2H, m), 1.58-1.50 (3H, m), 1.34 (6H, td, J=7.2 Hz),1.29-1.23 (3H, m); ¹³C NMR (100.5 MHz, CDCl₃) δ 77.1 (d, J=7.2 Hz), 63.4(d, J=6 Hz), 33.3 (d, J=4.5 Hz), 25.0 (d, J=7.5 Hz), 23.4, 16.1 (d,J=6.7 Hz); Spectroscopy data of the compound match with the datareported in the corresponding reference (Jones et al. (2003) J. Org.Chem. 68: 5211-5216).

xxiii. Diethyl benzylphosphoramidate (3W′)

27.2 mg, 56%; as a colorless oil; R_(f)=0.10 (ν_(DCM)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.26 (m, 5H), 4.11-3.94 (m, 6H), 3.40-3.30(m, 1H), 1.31-1.25 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 139.7 (d, J=6.7Hz), 128.5, 127.3, 127.2, 62.2 (d, J=5.2 Hz), 45.3, 16.1 (d, J=7.5 Hz);Spectroscopy data of the compound match with the data reported in thecorresponding reference (Kadina et al. (2015) Org. Lett. 17: 2586-2589).

xxiv. Diethyl cyclohexylphosphoramidate (3X′)

12.3 mg, 25%, as a colorless solid; R_(f)=0.2 (ν_(DCM)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 4.11-4.0 (4H, m), 2.99-2.95 (1H, m), 2.47 (1H,m), 1.94-1.90 (2H, m), 1.72-1.67 (2H, m), 1.59-1.55 (1H, m), 1.33-1.25(8H, m), 1.18-1.09 (3H, m); ¹³C NMR (100.5 MHz, CDCl₃) δ 62.1 (d,J=5.2), 50.5, 35.7 (d, J=5.2), 25.4, 24.9, 16.2 (d, J=6.7); Spectroscopydata of the compound match with the data reported in the correspondingreference (Kaboudin et al. (2015) Tetrahedron Lett. 56: 6364-6367).

xxv. Diethyl piperidin-1-ylphosphonate (3Y′)

4.2 mg, 10% as a yellow oil; R_(f)=0.2 (ν_(DCM)/ν_(EA)=2:1); ¹H NMR (400MHz, CDCl₃) δ 4.06-3.99 (4H, m), 3.12-3.07 (4H, m), 1.58-1.52 (6H, m),1.31, (6H, td, J=7.2); ¹³C NMR (100.5 MHz, CDCl₃) δ 61.9 (d, J=6.0 Hz),45.3 (d, J=2.0 Hz), 26.0 (d, J=5.2 Hz), 24.4, 16.2 (d, J=6.7 Hz);Spectroscopy data of the compound match with the data reported in thecorresponding reference (Dhineshkumar and Prabhu (2013) Org. Lett. 15:6062-6065).

xxvi. Diethyl phenylphosphoramidate (3Z′)

8.4 mg, 18% as a colorless solid; R_(f)=0.3 (ν_(EA)/ν_(Hexane)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.25 (2H, t, J=7.2 Hz), 7.01-6.94 (3H, m), 5.82(1H, d, J=8.0 Hz), 4.22-4.06 (4H, m), 1.32 (6H, t, J=7.2 Hz); ¹³C NMR(100.5 MHz, CDCl₃) 139.6, 129.3, 121.6, 117.2 (d, J=8 Hz), 62.7 (d,J=5.2 Hz), 16.1 (d, J=7.0 Hz); Spectroscopy data of the compound matchwith the data reported in the corresponding reference (Kaboudin et al.(2015) Tetrahedron Lett. 56: 6364-6367).

xxvii. O,O-Diethyl S-phenyl phosphorothioate (3AA′)

16.2 mg, 33%; as a colorless oil; R_(f)=0.20 (ν_(hexane)/ν_(EA)=2:1); ¹HNMR (400 MHz, CDCl₃) δ 7.59-7.54 (m, 2H), 7.37-7.32 (m, 3H), 4.27-4.10(m, 4H), 1.33-1.27 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 134.5 (d, J=5.3Hz), 129.3 (d, J=2.2 Hz), 128.9 (d, J=2.9 Hz), 126.6 (d, J=7.5 Hz), 64.0(d, J=6.0 Hz), 16.0 (d, J=7.4 Hz); Spectroscopy data of the compoundmatch with the data reported in the corresponding reference (Xu et al.(2016) Org. Lett. 18: 1266-1269).

d. General Procedure for the Synthesis of Mixed Diaryl Phosphates

i. Ethyl phenyl p-tolyl phosphate (4A′)

To a solution of diethyl phenyl phosphate 3a′ (46.3 mg, 0.2 mmol), Tf₂O(50.5 μL, 0.3 mmol) in DCM (1.0 mL) was added pyridine (32 μL, 0.4 mmol)in a 2-dram vial with a PTFE cap. After stirring for 10 min, p-cresol(43.2 mg, 0.4 mmol) was added to the reaction mixture. After stirringfor another 30 min at room temperature, the resulting mixture wasconcentrated to give the crude product which was then purified by columnchromatography on silica gel (PE/EA=5:1) to afford ethyl phenylbenzylphosphonate (3a′): 49.6 mg, 85%; as a colorless oil; R_(f)=0.20(ν_(Hexane)/ν_(EA)=5:1); ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H),7.25-7.15 (m, 3H), 7.14-7.08 (m, 4H), 4.35-4.27 (m, 2H), 2.32 (s, 3H),1.36 (td, J=6.8, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d,J=6.7 Hz), 148.4 (d, J=6.7 Hz), 134.9 (d, J=1.5 Hz), 130.2, 129.7,125.2, 120.0 (d, J=4.5 Hz), 119.7 (d, J=5.2 Hz), 65.4 (d, J=6.7 Hz),20.7, 16.0 (d, J=6.7 Hz); Spectroscopy data of the compound match withthe data reported in the corresponding reference (Dhawan and Redmore(1986) J. Org. Chem. 51: 179-183).

ii. Ethyl (4-methoxyphenyl) phenyl phosphate (4B′)

54.2 mg, 88%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3066, 2985, 2912, 1593, 1504, 1288, 1188, 1037, 956; ¹HNMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.24-7.12 (m, 5H), 6.86-6.81(m, 2H), 4.35-4.27 (m, 2H), 3.78 (s, 3H), 1.39-1.33 (m, 6H); ¹³C NMR(100.5 MHz, CDCl₃) δ 156.8, 150.6 (d, J=7.4 Hz), 144.1 (d, J=7.5 Hz),129.7, 125.2, 120.9 (d, J=4.5 Hz), 120.0 (d, J=4.5 Hz), 114.6, 65.4 (d,J=5.9 Hz), 55.6, 16.1 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ −10.78ppm; HRMS (ESI): m/z calcd. for C₁₅H₁₇O₅P ([M+H]⁺): 309.0886; Found:309.0876.

iii. 4-Bromophenyl ethyl phenyl phosphate (4C′)

58.3 mg, 82%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3066, 2985, 2912, 1589, 1485, 1292, 1195, 1165, 1041, 984;¹H NMR (400 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.37-7.31 (m, 2H),7.24-7.17 (m, 3H), 7.14-7.09 (m, 2H), 4.37-4.28 (m, 2H), 1.37 (td,J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.4 (d, J=7.5 Hz),149.6 (d, J=6.7 Hz), 132.7, 129.8 (d, J=6.0 Hz), 125.4 (d, J=1.5 Hz),121.9 (d, J=5.2 Hz), 120.0 (d, J=4.5 Hz), 118.2 (d, J=1.5 Hz), 65.7 (d,J=6.7 Hz), 16.0 (d, J=6.7 Hz); ³¹p NMR (162 MHz, CDCl₃): δ −11.50 ppm;HRMS (ESI): m/z calcd. for C₁₄H₁₄O₄PBr ([M+H]⁺): 356.9886; Found:356.9869.

iv. Ethyl (4-iodophenyl) phenyl phosphate (4D′)

61.3 mg, 76%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3066, 2981, 1589, 1481, 1288, 1226, 1195, 1165, 1041, 952;¹H NMR (400 MHz, CDCl₃) δ 7.66-7.61 (m, 2H), 7.37-7.31 (m, 2H),7.24-7.17 (m, 3H), 7.02-6.97 (m, 2H), 4.36-4.28 (m, 2H), 1.37 (td,J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.5 (d, J=6.7 Hz),150.4 (d, J=7.5 Hz), 138.8, 129.8, 125.4, 122.3 (d, J=5.2 Hz), 120.0 (d,J=4.5 Hz), 89.0, 65.7 (d, J=6.0 Hz), 16.1 (d, J=6.0 Hz); ³¹P NMR (162MHz, CDCl₃): δ −11.54 ppm; HRMS (ESI): m/z calcd. for C₁₄H₁₄O₄PI([M+Na]⁺): 426.9567; Found: 426.9569.

v. Ethyl phenyl (3-(trifluoromethyl)Phenyl) phosphate (4E′)

52.6 mg, 76%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3074, 2989, 2912, 1593, 1492, 1450, 1327, 1296, 1195,1130, 1041, 960; ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.42 (m, 4H), 7.38-7.32(m, 2H), 7.25-7.18 (m, 3H), 4.40-4.31 (m, 2H), 1.39 (td, J=7.2, 1.2 Hz,3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.7 (d, J=6.7 Hz), 150.3 (d, J=6.7Hz), 132.3 (q, J=33.5 Hz), 130.4, 129.9, 125.5, 123.5 (d, J=4.4 Hz),123.3 (d, J=270.9 Hz), 122.0 (m), 120.0 (d, J=5.2 Hz), 117.4 (m), 65.8(d, J=5.9 Hz), 16.0 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ −11.59ppm; HRMS (ESI): m/z calcd. for C₁₅H₁₄O₄F₃P ([M+H]⁺): 347.0655; Found:347.0640.

vi. 2-Cyanophenyl ethyl phenyl phosphate (4F′)

44.8 mg, 74%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=3:1); IRν (KBr, cm⁻¹) 3070, 2985, 2912, 2233, 1600, 1489, 1450, 1296, 1203,1184, 1165, 1037, 952; ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.62 (m, 1H),7.61-7.53 (m, 2H), 7.39-7.32 (m, 2H), 7.30-7.25 (m, 3H), 7.24-7.18 (m,1H), 4.49-4.40 (m, 2H), 1.42 (td, J=6.8, 1.2 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 152.0 (d, J=6.0 Hz), 150.2 (d, J=7.5 Hz), 134.4 (d, J=1.5Hz), 133.6, 129.9, 125.7, 125.4, 120.6 (d, J=3.0 Hz), 120.0 (d, J=4.5Hz), 115.0 (d, J=1.5 Hz), 105.6 (d, J=7.4 Hz), 66.5 (d, J=6.7 Hz), 16.0(d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ −12.50 ppm; HRMS (ESI): m/zcalcd. for C₁₅H₁₄NO₄P ([M+H]⁺): 304.0733; Found: 304.0724.

vii. [1,1′-Biphenyl]-4-yl ethyl phenyl phosphate (4G′)

46.4 mg, 80%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3059, 2985, 1593, 1516, 1485, 1292, 1226, 1195, 1165,1041, 952; ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m, 4H), 7.45-7.40 (m,2H), 7.38-7.23 (m, 7H), 7.22-7.16 (m, 1H), 4.39-4.30 (m, 2H), 1.39 (td,J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=7.5 Hz),150.0 (d, J=6.7 Hz), 140.1, 138.4, 129.8, 128.8, 128.4, 127.4, 127.0,125.3 (d, J=1.5 Hz), 120.3 (d, J=5.2 Hz), 120.1 (d, J=5.2 Hz), 65.6 (d,J=6.0 Hz), 16.1 (d, J=6.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ −11.22 ppm;HRMS (ESI): m/z calcd. for C₂₀H₁₉O₄P ([M+H]⁺): 355.1094; Found:355.1104.

viii. Ethyl naphthalen-1-yl phenyl phosphate (4H′)

47.9 mg, 73%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3062, 2985, 2908, 1597, 1489, 1392, 1292, 1207, 1087,1037, 948; ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.05 (m, 1H), 7.86-7.81 (m,1H), 7.67 (dd, J=8.4, 0.8 Hz, 1H), 7.53-7.48 (m, 3H), 7.40 (t, J=8.0 Hz,1H), 7.36-7.30 (m, 2H), 7.27-7.22 (m, 2H), 7.21-7.15 (m, 1H), 4.41-4.30(m, 2H), 1.35 (td, J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ150.6 (d, J=7.4 Hz), 146.5 (d, J=7.3 Hz), 134.7, 129.8, 127.7, 126.6,126.4, 126.3 (d, J=6.7 Hz), 125.4 (d, J=2.2 Hz), 125.3, 125.1 (d, J=1.5Hz), 121.6, 120.1 (d, J=5.2 Hz), 115.0 (d, J=3.0 Hz), 65.7 (d, J=5.9Hz), 16.1 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ −11.03 ppm; HRMS(ESI): m/z calcd. for C₁₈H₁₇O₄P ([M+H]⁺): 329.0937; Found: 329.0942.

ix. Ethyl naphthalen-2-yl phenyl phosphate (4I′)

55.7 mg, 85%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 3059, 2985, 2912, 1631, 1593, 1508, 1489, 1465, 1292,1041, 972; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=8.4 Hz, 2H), 7.79 (d,J=8.0 Hz, 1H), 7.70 (s, 1H), 7.51-7.42 (m, 2H), 7.37-7.31 (m, 3H),7.27-7.23 (m, 2H), 7.21-7.16 (m, 1H), 4.40-4.31 (m, 2H), 1.38 (td,J=7.2, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 150.6 (d, J=7.5 Hz),148.2 (d, J=7.5 Hz), 133.8, 131.0, 129.9, 129.8, 127.7, 127.6, 126.8,125.6, 125.3 (d, J=1.5 Hz), 120.1 (d, J=4.5 Hz), 119.9 (d, J=5.2 Hz),116.6 (d, J=4.5 Hz), 65.6 (d, J=6.7 Hz), 16.1 (d, J=6.7 Hz); ³¹P NMR(162 MHz, CDCl₃): δ −11.25 ppm; HRMS (ESI): m/z calcd. for C₁₈H₁₇₀₄P([M+H]⁺): 329.0937; Found: 329.0929.

x. Benzo [d][1,3]dioxol-5-yl ethyl phenyl phosphate (4J′)

52.1 mg, 81%; as a colorless oil; R_(f)=0.10 (ν_(Hexane)/ν_(EA)=5:1); IRν (KBr, cm⁻¹) 2985, 2904, 1593, 1485, 1292, 1246, 1126, 1037, 964; ¹HNMR (400 MHz, CDCl₃) δ 7.37-7.31 (m, 2H), 7.24-7.16 (m, 2H), 6.76-6.66(m, 3H), 5.96 (s, 2H), 4.35-4.27 (m, 2H), 1.37 (td, J=7.2, 1.2 Hz, 3H);¹³C NMR (100.5 MHz, CDCl₃) δ 150.6, 148.1, 144.9, 144.8, 129.7, 125.3(d, J=1.5 Hz), 120.0 (d, J=5.2 Hz), 112.5 (d, J=5.2 Hz), 108.0, 102.5(d, J=4.5 Hz), 101.7, 65.5 (d, J=6.0 Hz), 16.0 (d, J=6.0 Hz); ³¹P NMR(162 MHz, CDCl₃): δ −10.88 ppm; HRMS (ESI): m/z calcd. for C₁₅H₁₅O₆P([M+H]⁺): 323.0679; Found: 323.0687.

xi. (E)-Ethyl phenyl (4-(phenyldiazenyl)phenyl) phosphate (4K′)

66.4 mg, 87%; as a colorless oil; R_(f)=0.20 (ν_(Hexane)/ν_(EA)=3:1); IRν (KBr, cm⁻¹) 3066, 2985, 2908, 1593, 1489, 1296, 1230, 1192, 1041, 952;¹H NMR (400 MHz, CDCl₃) δ 7.96-7.88 (m, 4H), 7.54-7.44 (m, 3H),7.41-7.32 (m, 4H), 7.27-7.17 (m, 3H), 4.41-4.32 (m, 2H), 1.39 (td,J=7.6, 1.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 152.4 (d, J=2.2 Hz),150.4 (d, J=7.5 Hz), 149.8 (d, J=1.5 Hz), 131.1, 129.8, 129.1, 125.4 (d,J=1.5 Hz), 124.4, 122.8, 120.6 (d, J=5.2 Hz), 120.1, 120.0, 65.7 (d,J=6.7 Hz), 16.1 (d, J=6.7 Hz); ³¹p NMR (162 MHz, CDCl₃): δ −11.68 ppm;HRMS (ESI): m/z calcd. for C₂₀H₁₉N₂O₄P ([M+H]⁺): 383.1155; Found:383.1152.

e. General Procedure for the Synthesis of Aryl Phosphinate

i. p-tolyl diphenylphosphinate (5A′)

To a solution of ethyl diphenylphosphinate 1c′ (49.3 mg, 0.2 mmol), Tf₂O(50.5 μL, 0.3 mmol) in DCM (1.0 mL) was added pyridine (32 μL, 0.4 mmol)in a 2-dram vial with a PTFE cap. After stirring for 10 min, p-cresol(43.6 mg, 0.4 mmol) was added to the reaction mixture. After stirringfor another 30 min at room temperature, the resulting mixture wasconcentrated to give the crude product which was then purified by columnchromatography on silica gel (PE/EA=5:1) to afford p-Tolyldiphenylphosphinate (5^(a)′): 45.6 mg, 74%; as a colorless oil;R_(f)=0.50 (ν_(Hexane)/ν_(EA)=1:1); ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.84(m, 4H), 7.56-7.42 (m, 6H), 7.11-6.98 (m, 4H), 2.23 (s, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 148.6 (d, J=7.4 Hz), 134.0, 132.3 (d, J=3.0 Hz),131.8 (d, J=10.4 Hz), 131.1 (d, J=137.0 Hz), 130.1, 128.6, 128.4, 120.4(d, J=4.5 Hz), 20.6; Spectroscopy data of the compound match with thedata reported in the corresponding reference (Xiong et al. (2015) ACSCatal. 5: 537-543).

f. Large-Scale Experiment

To a solution of triethyl phosphate 1a′ (1.08 g, 6.0 mmol) in DCM (30mL) was added Tf₂O (1.50 mL, 9.0 mmol) and pyridine (1.00 mL 12.0 mmol)in a 48 mL glass tube (Figure S1, tube C). The resulting mixture wasstirred for 10 min. After stirring for 10 min, phenol (1.14 g, 12.0mmol) was added to the tube under. After stirring for another 1 h, theresulting solution was concentrated to give the crude product which waspurified by column chromatography on silica gel (PE/EA=3:1-2:1) toafford 3a′ (1.24 g, 90%).

g. Continuous Flow Chemistry

All tubings, connectors and needles were purchased from VWRinternational, unless otherwise stated. Syringe pump was purchased fromKD Scientific—The Syringe Pump Company. The equipment configurationsthat were used for the flow reactions are depicted in Figure S2. Thetubing reactors and all connecting tubings in all figures useChemfluor®PTFE Fluoropolymer Tubing ( 1/16″I.D.×⅛″ O.D.).

h. General Procedure for Flow Synthesis Experiment in 2 mmol Scale (3a′as Example)

Syringe A was loaded with a solution of phosphoryl pyridine-1-ium (0.4M) in DCM and then fitted to a syringe pump. Syringe B was loaded with asolution of phenol 2a′ (0.8 M) in DCM and then fitted to a same syringepump. Following the setup as shown in Figure S2, the solutions ofphosphoryl pyridine-1-ium and 2a′ were injected in the tubing reactorover 30 min. After reaching steady state for 30 min, the reactionmixtures were collected by argon purging into a flask. The collectedsolution was evaporated under reduced pressure, and the residue waspurified by flash column chromatography on silica gel (eluent: fromhexane to hexane:EA=2:1) to give the colorless oil product 3a′: 358 mgin 78% yield.

2. Synthesis of Mixed Phosphonates a. Initial Screening of Nucleophiles

To test the hypothesis, Tf₂O, pyridine, and diethyl benzylphosphonate 1awere utilized to screen nucleophiles and the outcomes are shown inScheme 1 below. When Grignard reagent and morpholine were employed asnucleophiles, a mixture of unidentified compounds were generated.Thiophenol and 2-naphtol substrates, in which only thiophenol triflateand morpholine triflate were isolated in 35% and 37% yields,respectively, also failed to give the corresponding mixed phosphonates.Notably, when phenol was introduced as a nucleophile, mixed phosphonate3a was furnished in 77% NMR yield, which evidenced a new potential routefor mixed phosphonate synthesis. With promising initial results, it wasdecided to further explore this direct aryloxylation of various dialkylphosphonates.

b. Optimization of Reaction Conditions

Optimization of the reaction conditions was carried out with diethylbenzylphosphonate 1a and phenol 2a. Initially, pre-activation time forthe generation of the intermediate III shown in FIG. 3 was studied. Itwas found that a pre-reaction time of 10 min prior to the addition of 2ato a mixture of 1a and Tf₂O/pyridine is required for high yields (Table1, entry 1). Screening of other bases did not improve the product yieldbut a phenyl triflate byproduct was formed. In contrast, there was notarget product without bases (Table 1, entry 2). Among the screenedsolvents, DCM is superior to other solvents (Table 1, entries 3-8).Further optimization revealed that the highest yield of 3a (99% yield byNMR) could be achieved with an excess of Tf₂O (1.5 equiv), pyridine (2.0equiv), and phenol 2a (2.5 equiv) (Table 1, entry 9).

TABLE 1

yield entry base solvent X:Y:Z (%)^([a]) 1 pyridine DCM 2.0:2.0:2.0 85 2— DCM 2.0:2.0:2.0 NR 3 pyridine CHCl₃ 2.0:2.0:2.0 37 4 pyridine DCE2.0:2.0:2.0 49 5 pyridine Et₂O 2.0:2.0:2.0 46 6 pyridine toluene2.0:2.0:2.0 36 7 pyridine THF 2.0:2.0:2.0 NR 8 pyridine CH₃CN2.0:2.0:2.0 trace 9 pyridine DCM 1.5:2.0:2.5 99(92) ^([b]) Reactionconditions: 1a (0.2 mmol), Tf₂O (X equiv), base (Y equiv) in solvent(1.0 mL) for 10 min, then PhOH (Z equiv) for 30 min. ^([a])Yield wasdetermined by ¹H NMR on the crude reaction mixture using1,3,5-trimethylbenzene as an internal standard. ^([b])Isolated yield.

c. Exploration of Reaction Scope

With the optimized reaction conditions in hand, the scope of thereaction was explored with diverse dialkyl phosphonates 1, demonstratingefficient substrates to form mixed alkyl aryl phosphonates 3a-3x (Scheme2). Different substituents on the benzyl group were well tolerated(86-94% yields) (Scheme 2, 3a-3g). Phosphonates with aliphaticsubstituents 1h-1j are also suitable substrates for this reaction toprovide alkyl-substituted mixed phosphonates 3h-3j in 85-90% yields. Inaddition, phenyl phosphonates 1k-1n with different alkoxy substituentsMeO, EtO, i-PrO, and n-BuO were examined, and they afforded thecorresponding mixed phosphonates 3k-3n in 81-93% yields. In line withthe hypothesis of favoring electron-rich substituents on the phosphonatemotif for the activation with Tf₂O, the electronic effects of the phenylsubstituents on the phosphonates have significant influence on theproduct yield: for example, an electron-deficient phosphonate 1o with ap-nitro phenyl substituent provided the product 3o in 28% yield (Scheme2). This reaction shows broad compatibility with a diverse array ofsubstrates bearing halide, allylic, vinyl, alkyne, and diene groups(Scheme 2, 3p-3v). A heteroaromatic phosphonate was also efficientlytransformed to the desired mixed phosphonate 3w in 83% yield.Importantly, the synthesis of O-ethyl O-, S-diphenyl phosphorothioate 3xknown as a classical antibacterial agent (Kazuo et al. JP 48018461 B19730606, 1973) was demonstrated by this system with 81% yield.

Next, the scope was investigated with respect to phenol derivatives. Thereaction tolerates both electron-donating groups (Me, MeO) andelectron-deficient substituents (Br, I, NO₂, CF₃) on the phenyl ring,providing the desired products in high yields (Scheme 2, 4a-4h). Ortho-,para-substituted dichlorophenol was a suitable substrate for thistransformation to afford 4i in 77% yield. In contrast, having bulkygroups on 2-, 6-positions on phenols significantly reduced the productyields (Scheme 2, 4k-41). As compared to initial experimental resultswith no pre-activation process, polycyclic aromatic alcohols such as1-naphthol, 2-naphthol, and quinolin-6-ol proved to be suitablesubstrates under the optimized reaction conditions, affording the mixedphosphonates 4n-4p in 70-87% yields. In addition, this method toleratesa wide range of functional groups (e.g., ester, carbonate, allyl, azo,and acrylate) on the phenol (Scheme 2, 4q-4u). Especially, the reactionof 1a with cholesterol-derived phenol proceeded efficiently to give 4vas a phosphonylated cholesteryl ester derivative bearing a biologicallyimportant mixed phosphonate scaffold in 84% yield (Scheme 2, 4v).

With a demonstration of aryloxylation of phosphonates with variousphenol derivatives, the reactivity of aliphatic alcohols under the samereaction conditions was explored (Scheme 2). It was found that variousalcohols such as 1° alcohols and 2° alcohol were all efficiently coupledwith dialkylphosphonates to provide mixed phosphonates 5a-5h in moderateto high yields.

Next, late-stage phosphonylation of various natural products wasinvestigated to demonstrate functionalization of bioactive smallmolecules (Scheme 2). The phosphonylation reaction of natural compoundssuch as coumarin 2af, ferulate 2ag, and estradiol 2ah exhibited goodfunctional group tolerance (e.g., ester, acrylate, ether, and hydroxylgroup) and provided the corresponding products in moderate to highyields (Scheme 2, 6a-6c). It is worth mentioning that this protocolshows an excellent chemoselectivity with estradiol 2ah bearing both arylalcohol and aliphatic alcohol, providing only 6c with 41% yield. Inaddition, sesamol 2ai afforded the corresponding mixed phosphonate 6d inexcellent yield (90% yield). An enol nucleophile of maltol was also asuitable coupling partner for this transformation to furnish the desiredmixed phosphonate 6e in 51% yield. Finally, aliphatic alcohol-containingnatural product cholesterol 2ak was subjected to the standard reactionconditions, and the target mixed phosphonate product 6f (Kalek et al.(2008) Org. Lett. 10: 4637) was isolated with 81% yield.

d. Potential Applications to Pharmaceuticals and Organic Synthesis

To demonstrate the potential application of this synthetic protocol topharmaceuticals and organic synthesis, a larger-scale reaction of 11(1.07 g, 5.0 mmol) with 2a was performed, which afforded the targetmixed phosphonate 31 (1.26 g) in 96% yield along with 52% recovery ofthe phenol 2a. 2-Hydroxybenzonitrile 2al was also a suitable substrateand generated a functionalized phosphonate 7a (87% yield), which is akey precursor for meta-C—H activation of the benzene ring to givemulti-substituted benzene compounds 7aa (Scheme 3, a; Bera et al. (2016)ACS Catal. 6: 3575; Bag et al. (2017) Angew. Chem. Int. Ed. 56: 12538;Ange. Chem. 129: 12712). Next, the aryloxylation protocol was applied tothe synthesis of a key intermediate of butyrophilin ligand prodrug 7bbreported by the Wiemer group. The transformation achieved one stepsynthesis of 7b from 1x and 2o and enables higher yield (84%) in shortreaction time (40 min) (Scheme 3, b; Foust et al. (2017) ACS Med. Chem.Lett. 8: 914). Finally, a mixed phosphonate 7c, a key intermediate ofpolymer immobilized enzyme inhibitors 7cc, was also successfullysynthesized in 87% yield from 1y and 2f (Scheme 3, c; Reetz et al.(2002) Tetrahedron 58: 8465).

e. In Situ NMR Study of the Mechanism of Aryloxylation of Phosphonates

It was initially proposed that a highly reactive P-species such as theintermediate III (FIG. 3) could be generated in the reaction process. Togain evidence for the formation of the intermediate III and tounderstand a plausible mechanism, in situ NMR studies of the reaction ofdiethyl benzylphosphonate 1a and phenol 2a with Tf₂O and pyridine wereperformed (FIG. 4). When TfO₂ was added to 1a, peaks corresponding to 1a(FIG. 4, spectrum a) disappeared rapidly within 2 min. and three newmajor peaks (diamond marks) appeared (FIG. 4, spectrum b). It wasproposed that these signals should belong to phosphonium 3aa based onthe peak ratios and relative chemical shifts as well as the J-values ofthe benzylic and methylene protons, which were the same as those in 1a.The corresponding ¹H NMR spectra showed that phosphonium intermediate3aa is quickly converted into the intermediate 3ab (star marks) within 5min. (FIG. 4, spectrum c; Dahl (1982) Tetrahedron Lett. 23: 1493-1496).Intermediate 3ab, however, failed to give the desired mixed phosphonateproduct when it was directly treated with phenol 2a, implying that 3abis not a highly reactive intermediate toward aryloxylation reaction ofphosphonates. Interestingly, a number of new peaks appeared on the ¹HNMR spectra after the addition of pyridine, accompanied by precipitationin the NMR tube. With this observation and a chemical shift of 30.7 ppmin the ³¹P NMR spectrum, it was suggested that a phosphorylpyridin-1-ium salt 3ac (hollow circles) is formed (FIG. 4, spectrum d).In fact, mixed phosphonate 3a (filled circles) was formed when phenol 2awas introduced to intermediate 3ac (FIG. 4, spectrum e). Phosphorylpyridine-1-ium 3ac is not only highly reactive but also sensitive. Whenthe crude mixture of 3ae was kept at rt for 2 h, 3ae was completelydecomposed to ethyl triflate A and pyridinium salt B, as clearlypresented on the ¹H NMR spectra (FIG. 4, spectrum f).

f. Proposed Mechanism Based on the NMR Study

Based on the NMR study, a plausible mechanism is proposed (Scheme 4,path a). The terminal oxygen of the phosponate ¹⁸O-1a attacks the Tf₂Oto furnish a phosphonium intermediate I. Next, TfO-substitutedphosphonate II and ethyl triflate by-product are generated by attackingthe triflate anion on the carbon atom of the alkoxy group ofintermediate I. Then, the pyridine nucleophile attacks intermediate IIto form a highly reactive electrophilic phosphorous species ofphosphoryl pyridin-1-ium III (Hendsbee et al. (2012) Angew. Chem. Int.Ed. 51: 10836; Huynh et al. (2007) J. Am. Chem. Soc. 128: 5930; Cui etal. (2017) Inorganica Chimica Acta 460: 2). Finally, intermediate III istransformed to mixed phosphonate 3a by substitution reaction withhydroxyl nucleophile 2a (Weiss et al. (2008) J. Am. Chem. Soc. 130:4610; Fujioka et al. (2006) J. Am. Chem. Soc. 128: 5930; Quesnel et al.(2016) Chem. Sci. 7: 295). An alternative mechanism is also described(Scheme 4, path b). The bridging oxygen of 1a attacks the Tf₂O,resulting in the formation of intermediate Ia. The triflate anion thenattacks the carbon atom activated by the positively charged oxygen atomin Ia to form the TfO-substituted phosphonate IIa. Then, theintermediate IIa is converted to the mixed phosphonate product ¹⁸O-3avia intermediate IIIa by following the remaining same mechanistic stepsof path a.

Nevertheless, there are two important mechanistic aspects that need tobe considered rigorously. First, what type of substitution reactions(S_(N)1 versus S_(N)2) take place to transform the intermediate I to II?Second, which oxygen atom (terminal oxygen, path a versus internaloxygen, path b) is activated by Tf₂O? To take these into account,isopropyl methyl phenylphosphonate 5e was employed under the optimizedreaction conditions, and only the isopropyl group was substituted togive 3k (Scheme 5, a). Therefore, it was proposed that this substitutionreaction might follow an S_(N)1-type mechanism. Next, to address theactivation process of the phosphonate with Tf₂O, a 1:1 mixture ofdiethyl phenylphosphonate 1l and diethyl (4-nitrophenyl)phosphonate 1ywas treated with phenol 2a under the standard reaction conditions. Only11 was converted into the mixed phosphonate 31 with 88% yield andunreacted 1y was recovered with 83% (Scheme 5, b). This outcomegenerated in 83% yield when ¹⁸O-1l dialkyl phosphonate was employed(Scheme 5, c; Blazewska (2014) J. Org. Chem. 79: 408), which stronglysupports that this transformation should follow the proposed mechanismof path α shown in Scheme 4.

g. Proposed Mechanism Based on Experimental Data and Density FunctionalTheory Calculations

Based on the experimental data and density functional theory (DFT)calculations, a plausible mechanism is proposed in Scheme 6. Theterminal oxygen of the phosphonate 1a attacks the Tf₂O via TS1 tofurnish a phosphonium intermediate I. Next, TfO-substituted phosphonateII and ethyl triflate byproduct are generated via S_(N)l-type mechanismfrom the intermediate I (Fañanás-Mastral and Feringa (2014) J. Am. Chem.Soc. 136: 9894; Nielson and Caruthers (1988) J. Am. Chem. Soc. 110:6275). Then, the pyridine nucleophile attacks the intermediate II toform a highly reactive electrophilic phosphorus species of phosphorylpyridin-1-ium III (Hendsbee et al. (2012) Angew. Chem. Int. Ed. 51:10836; Angew. Chem. 124: 10994; Huynh et al. (2007) Inorg. Chem. 46:9979; Cui et al. (2017) Inorg. Chim. Acta 460: 2). Finally, thisintermediate III is transformed to the mixed phosphonate 3a bysubstitution reaction with phenol 2a through the TS2 (Li et al. (2015)Tetrahedron Lett. 56: 4694; Ladame et al. (2001) Phosphorous SulfiurSilicon Relat. Elem. 174: 37; Weiss et al. (2008) J. Am. Chem. Soc. 130:4610; Fujioka et al. (2006) J. Am. Chem. Soc. 128: 5930; supports thatthe terminal oxygen of phosphonates may serve as a nucleophilic atom toreact with Tf₂O (Fañanás-Mastral and Feringa (2014) J Am. Chem. Soc.136: 9894). Furthermore, as shown in Scheme 4, ¹⁸O-labeled phosphonate¹⁸O-1a would generate a non-labeled product 3a through path α, while¹⁸O-labeled phosphonate ¹⁸O-3a could be generated from the ¹⁸O-1a viapath b. Subsequently, control experiments with ¹⁸O-1l was performed tosee if the non-labeled product 31 could be obtained. In fact, thenon-labeled product 31 was generated in 83% yield when ¹⁸O-1l dialkylphosphonate was employed (Scheme 5, c; Blazewska (2014) J. Org. Chem.79: 408), which strongly supports that this transformation should followthe proposed mechanism of path α shown in Scheme 4.

g. Proposed Mechanism Based on Experimental Data and Density FunctionalTheory Calculations

Based on the experimental data and density functional theory (DFT)calculations, a plausible mechanism is proposed in Scheme 6. Theterminal oxygen of the phosphonate 1a attacks the Tf₂O via TS1 tofurnish a phosphonium intermediate I. Next, TfO-substituted phosphonateII and ethyl triflate byproduct are generated via S_(N)1-type mechanismfrom the intermediate I (Fañanás-Mastral and Feringa (2014) J. Am. Chem.Soc. 136: 9894; Nielson and Caruthers (1988) J. Am. Chem. Soc. 110:6275). Then, the pyridine nucleophile attacks the intermediate II toform a highly reactive electrophilic phosphorus species of phosphorylpyridin-1-ium III (Hendsbee et al. (2012) Angew. Chem. Int. Ed. 51:10836; Angew. Chem. 124: 10994; Huynh et al. (2007) Inorg. Chem. 46:9979; Cui et al. (2017) Inorg. Chim. Acta 460: 2). Finally, thisintermediate III is transformed to the mixed phosphonate 3a bysubstitution reaction with phenol 2a through the TS2 (Li et al. (2015)Tetrahedron Lett. 56: 4694; Ladame et al. (2001) Phosphorous SulfurSilicon Relat. Elem. 174: 37; Weiss et al. (2008) J. Am. Chem. Soc. 130:4610; Fujioka et al. (2006) J. Am. Chem. Soc. 128: 5930; 182(a) Quesnelet al. (2016) Chem. Sci. 7: 295; Hoque et al. (2007) J. Org. Chem. 72:5493; Edwards et al. (2012) J. Phys. Org. Chem. 25: 258; Guha and Lee(1999) J. Chem. Soc. Perkin Trans. 2, 765; Nilsson et al. (2001) J.Chem. Soc. Perkin Trans. 2, 2263; Dabkowski et al. (1985) Chem. Ber.118: 1809; Smith et al. (2000) Org. Lett. 2: 3887; Kolodiazhnyi andKolodiazhna (2017) Tetrahedron. Asymmetry 28: 1651; Also, it is notedthat the 5-coordinate intermediate TS2′ below was ruled out because itwas free energy 1.3 kcal mol⁻¹ above TS2 and enthalpy 14.1 kcal mol⁻¹above TS2).

In summary, a mild, efficient, direct aryloxylation/alkyloxylation ofdialkyl phosphonates for the synthesis of mixed phosphonates has beendeveloped. This synthetic transformation enabled the synthesis of a widerange of functional mixed phosphonates without the use of metal orchloride reagents. In this chemistry, it was demonstrated that aphosphoryl pyridin-1-ium, a highly electrophilic P-species of powerfulphosphonylation reagent for the synthesis of mixed phosphonates, can begenerated from dialkyl phosphonates with Tf₂O/pyridine. The syntheticutility of this transformation was demonstrated by the synthesis of keyintermediates of bioactive compounds (butyrophilin ligand prodrug andenzyme inhibitors) and the late-stage phosphonylation of naturalcompounds.

3. Synthesis of Mixed Phosphates and Phosphinates a. Optimization ofReaction Conditions

To test the hypothesis, triethyl phosphate 1a′ and phenol 2a′ were usedas model substrates to optimize the reaction conditions (Table 2).Gratifyingly, the desired phenyl phosphate 3a′ was generated in 96%yield by NMR when our previous optimized reaction conditions for mixedphosphonate was employed (Table 2, entry 1). Further control experimentsrevealed that the optimized reaction conditions need 2 equivalents ofphenol 2a′, providing the target compound with 92% isolated yield (Table2, entries 2-6). Evaluation of other bases such as lutidine, DMAP,DABCO, and DBU provided no target products (Table 2, entries 7-10).

TABLE 2

entry base X:Y:Z yield (%)^(a) 1 pyridine 1.5:2.0:2.5 96 2 pyridine1.5:2.0:2.0 99(92)^(b) 3 pyridine 1.5:2.0:1.5 43 4 pyridine 2.0:2.0:2.092 5 pyridine 1.5:1.1:2.0 80 6 pyridine 1.5:1.5:2.0 70 7 lutidine1.5:2.0:2.0 —^(c) 8 DMAP 1.5:2.0:2.0 —^(c) 9 DABCO 1.5:2.0:2.0 —^(c) 10DBU 1.5:2.0:2.0 —^(c) Reaction conditions: 1a′ (0.2 mmol), Tf₂O (Xequiv), base (Y equiv) in solvent (1.0 mL) for 10 min, then 2a′ (Zequiv) for 30 min. ^(a)Yield was determined by ¹H NMR on the crudereaction mixture using 1,3,5-trimethylbenzene as an internal standard.^(b)Isolated yield. ^(c)Major product was PhOTf.

b. Exploration of Reaction Scope

With the optimized reaction conditions in hand, the scope of thisreaction was explored with phosphates 1′ and diverse arenol nucleophiles2′ to synthesize phosphate derivatives 3′. To demonstrate scalability ofthis reaction, a gram-scale reaction of 1a′ (1.09 g, 6.0 mmol) with 2a′was performed first, which afforded the target phosphonate product 3a′(1.24 g) in 90% yield (Scheme 7, 3a′). Generally, the electronic effectsof substituents on the phenyl ring have a negligible effect on thistransformation. The reaction tolerates various phenols with diversesubstituents (Me, MeO, Br, I, NO₂, Ph) and polycyclic aromatic alcoholssuch as 1-naphthol and 2-naphthol, providing the desired aryl phosphateswith 71-91% yields (Scheme 7, 3b′-3k′). However, a bulky nucleophilesuch as 2,6-di-isopropyl phenol reduced the reactivity and provided thetarget product 3m′ with 53% yield due to steric hindrance. On the otherhand, a sterically bulky phosphate electrophile, triisopropyl phosphate1b′, afforded the corresponding diisopropyl phosphate 3n′ in 73% yield(Scheme 7, 3n′).

Next, the late-stage phosphorylation of various natural products wasinvestigated. The phosphorylation of quinol, coumarin, sesamol, andferulate demonstrated good functional group tolerance (e.g., carbonate,ester, ether, and acrylate), yielding the corresponding products in highyields (Scheme 7, 3o′-3r′). Importantly, the reaction of 1a′ with acholesterol-derived phenol provided a phosphorylated cholesteryl ester3s′ with a biologically important phosphate moiety in 76% yield (Scheme7, 3s′). Furthermore, the reactivity of other nucleophiles was evaluatedunder the standard reaction conditions (Scheme 7, 3t′-3z′). Both primaryand secondary aliphatic alcohols were also efficiently coupled with thephosphate 1a′ to yield alkyl phosphates 3t′-3v′ in 49-87% yields.Finally, it was demonstrated that amine and thiol nucleophiles can beemployed in this transformation to provide the azaphosphates 3w′-3z′ andthiophosphate 3aa′ in acceptable to moderate yields (Scheme 7).

The synthesis of mixed diaryl phosphates from aryl dialkylphosphates isa challenging synthetic transformation in organophosphate chemistrysince it requires an exquisite control of reactivity andchemoselectivity to prevent dual substitution reaction of the two alkoxygroups (Takeuchi et al. (1979) Tetrahedron Lett. 20: 1231; Blackburn andIngleson (1980) J. Chem. Soc., Perkin Trans. 1, 1150-1153; Chowdhury etal. (2007) Bioorg. Med. Chem. Lett. 17: 3745; Koster et al. (1983) J.Am. Chem. Soc. 105: 3743; Blackburn and Ingleson (1978) J. Chem. Soc.,Chem. Commun., 870-871; Cooke and Gerrard (1955) J. Chem. Soc.,1978-1982; Sevrain et al. (2017) Beilstein J. Org. Chem. 13: 2186).Hence, a selective synthesis of mixed diaryl phosphates from aryldialkylphosphates was explored as shown in Scheme 8. Phenyl phosphate3a′ was used as a starting material and it was efficiently coupled witharenols bearing different substituents such as methyl, halo, CN, CF₃,and aryl groups to afford the corresponding mixed diarylphosphates4a′-4g′ in 74-88% yields. 1-naphthol and 2-naphthol were also proved tobe suitable substrates under the standard reaction conditions, providingthe mixed diarylphosphates 4h′ and 4i′ in 73% and 85% yields,respectively. In addition, a natural compound sesamol also furnished thecorresponding mixed diaryl phosphate 4j′ in 81% yield. Furthermore, thisreaction tolerates an azo functional group on a phenyl ring, whichgenerated the desired product 4k′ in high yield (87%).

Finally, this synthetic protocol has been successfully applied for theconversion of an alkylphosphinate to an arylphosphinate (Nora and Gyorgy(2014) Curr. Org. Chem. 18: 2673; Virieux et al. (2015) Top. Curr. Chem.360: 39), demonstrating a general activating procedure of all threedifferent oxygen-containing pentavalent phosphorus compounds(phosphates, phosphonates (Huang et al. (2018) Angew. Chem. Int. Ed. 57:6624), and phosphinates). When diphenyl ethylphosphinate 1c′ was treatedwith p-cresol, the target arylphosphinate 5a′ was obtained in 74% yield(Scheme 9).

c. Continuous Flow System for Phosphate Synthesis

With the potential application of this versatile synthetictransformation (short reaction time, high tolerance of functionalgroups, and mild reaction conditions) to chemical enterprise, thedevelopment of a continuous flow synthesis system was explored tofurther demonstrate the synthetic utility of this methodology (Xiong etal. (2015) ACS Catal. 5: 537; Whitesides (2006) Nature 442: 368;Dudukovic et al. (1999) Chem. Eng. Sci. 54: 1975). While enzymaticsynthesis of phosphorylated compounds via continuous-flow reactor hasbeen reported (Babich et al. (2013) Int. J. Chem., 5; Babich et al.(2012) Chem. Eur. J. 18: 6604), chemical synthesis of phosphoruscompounds using flow chemistry is underdeveloped. Hence, anaryloxylation reaction was conducted to test amenability in acontinuous-flow reactor as described in FIG. 5. This continuous-flowprocedure efficiently furnished the desired aryl phosphate 3a′ in 78%yield. In addition, a natural compound sesamol can also afford thecorresponding phosphate 3q′ in moderate yield (42% yield) under thiscontinuous-flow system.

In summary, a new synthetic strategy for the activation of pentavalentorganophosphorus compounds (phosphate, phosphinate) in which aphosphoryl pyridin-1-ium intermediate is generated in situ from aphosphate with Tf₂O/pyridine has been developed. This electrophilicP-species efficiently undergoes nucleophilic substitution reaction withvarious nucleophiles (aliphatic alcohols, arenols, amines, and thiols)to provide functional phosphate compounds under metal-free reactionconditions. The synthetic utility of this phosphorylation has beendemonstrated by late-stage phosphorylation of natural compounds. Inaddition, a continuous flow system for the synthesis of phosphates hasbeen demonstrated. Further studies on the development of efficientsynthesis of functional phosphorus compounds based on the in situgenerated P-species especially for improving the product yields ofazaphosphates and thiophosphates are underway.

4. Synthesis of Mixed Thiophosphates and Thiophosphates a. Optimizationof Reaction Conditions

A summary of the reaction conditions explored with respect tothiophosphate analogs is shown in Table 3 below.

TABLE 3

Addition of Yield Entry A PhOH Tf₂O Pyridine Nucleophile Temp. (%) 1 1.02.5 1.5 2.0 15 min rt 80 2 1.0 2.5 1.5 2.0 10 min rt 70 3 1.0 2.5 1.52.0 30 min rt 63 4 1.0 2.0 1.5 2.0 15 min rt 64 5 1.0 3.0 1.5 2.0 15 minrt 87 6 1.0 3.0 2.0 2.0 15 min rt 15 7 1.0 3.0 1.2 2.0 15 min rt 44 81.0 3.0 1.5 2.5 15 min rt 59 9 1.0 3.0 1.5 1.5 15 min rt 35 10 1.0 3.01.5 1.5 15 min 0° C. 60

b. Exploration of Reaction Scope

The scope of the reaction was explored with a variety of electrophiles(Scheme 10) and nucleophiles (Scheme 11).

5. Selective Dealkylation of Phosphates

The selective dealkylation of phosphates is illustrated in Scheme 12below.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otheraspects of the invention will be apparent to those skilled in the artfrom consideration of the specification and practice of the inventiondisclosed herein. It is intended that the specification and examples beconsidered as exemplary only, with a true scope and spirit of theinvention being indicated by the following claims.

What is claimed is:
 1. A method of making a compound having a structurerepresented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)Ar¹,(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³⁰, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(3la)R^(3lb), —NH(C═O)NR^(3la)R^(3lb),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(3la) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein R² isselected from hydrogen, C1-C8 alkyl substituted with 0-1 phenyl groups,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar²,—(C2-C4 alkenyl)Ar², —(C2-C4 alkynyl)Ar², Ar², and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl groups; wherein Ar², when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³ when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl, or a salt thereof, the methodcomprising the step of reacting a phosphonate derivative having astructure represented by a formula:

wherein R⁴ is C1-C4 alkyl, provided that R² and R⁴ are different, or asalt thereof, with a nucleophile having a structure represented by aformula:

in the presence of an activating agent, wherein the activating agent isselected from triflic anhydride, mesyl chloride, tosyl chloride, oxalylchloride, thionyl chloride, acetic anhydride, benzoic anhydride, andtrifluoroacetic anhydride, and a base.
 2. The method of claim 1, whereinthe compound has a structure represented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, and CHR²¹; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Q isselected from O, S, and NR²²; wherein R²², when present, is selectedfrom hydrogen and C1-C8 alkyl; wherein R¹ is selected from —(C1-C4alkyl)Ar¹ and Ar¹; wherein Ar¹, when present, is selected from aryl andheteroaryl and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl),—OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³⁰,—(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4 alkyl),—(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b), —O(C═O)NR^(31a)R^(31b),—NHSO₂NR^(3la)R^(3lb), —NH(C═O)NR^(3la)R^(3lb), and —N=NR³²; whereinR³⁰, when present, is selected from hydrogen, C1-C8 alkyl, —(C1-C4alkyl)phenyl, phenyl, and a structure represented by a formula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein R² is selected from —(C1-C4 alkyl)Ar² and Ar²; whereinAr², when present, is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(3th), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein R³ is C1-C4 alkyl.
 3. The method of claim 1, whereinthe compound is selected from:


4. The method of claim 1, wherein the compound is selected from:


5. The method of claim 1, wherein the compound is selected from:


6. The method of claim 1, wherein the compound is selected from:


7. The method of claim 1, wherein the activating agent is triflicanhydride.
 8. The method of claim 1, wherein the base is pyridine.
 9. Amethod of making a compound having a structure represented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, NR²⁰, and CHR²¹;wherein R²⁰, when present, is selected from hydrogen and methyl; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from C1-C8 alkyl,C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar¹,—(C2-C4 alkenyl)Ar¹, —(C2-C4 alkynyl)Ar¹, Ar¹, and a structurerepresented by a formula selected from:

and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or1 C1-C4 alkyl group; wherein Ar¹, when present, is selected from aryland heteroaryl and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4 alkyl)CO₂R³⁰, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(3la)R^(3lb), —NH(C═O)NR^(3la)R^(3lb),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(3la) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; or wherein each of R¹ and R²⁰, when present, are optionallycovalently bonded together and, together with the intermediate carbonatoms, comprise a 3- to 6-membered heterocycloalkyl; wherein Ar² isselected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl,—O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4 alkyl)CO₂R³³, —(C2-C4alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO₂(C1-C4alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar³ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl, or a salt thereof, the method comprising the step of reacting aphosphinate derivative having a structure represented by a formula:

wherein R³ is C1-C4 alkyl, or a salt thereof, with a nucleophile havinga structure represented by a formula:

in the presence of an activating agent, wherein the activating agent isselected from triflic anhydride, mesyl chloride, tosyl chloride, oxalylchloride, thionyl chloride, acetic anhydride, benzoic anhydride, andtrifluoroacetic anhydride, and a base.
 10. The method of claim 9,wherein the compound has a structure represented by a formula:

wherein n is 0 or 1; wherein A is selected from O, S, and CHR²¹; whereinR²¹, when present, is selected from hydrogen and methyl; wherein Z isselected from O, S, and NR²³; wherein R²³, when present, is selectedfrom hydrogen and methyl; wherein R¹ is selected from —(C1-C4 alkyl)Ar¹and Ar¹; wherein Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁰, —CO₂R³⁰, —(C1-C4alkyl)CO₂R³⁰, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(31a)R^(31b), —SO₂NR^(31a)R^(31b),—O(C═O)NR^(31a)R^(31b), —NHSO₂NR^(3la)R^(3th), —NH(C═O)NR^(3la)R^(3lb),and —N═NR³²; wherein R³⁰, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(31a) and R^(31b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³², when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; wherein Ar², when present, is selected from aryl and heteroaryland is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³³, —CO₂R³³, —(C1-C4alkyl)CO₂R³³, —(C2-C4 alkenyl)CO₂R³³, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(34a)R^(34b), —SO₂NR^(34a)R^(34b),—O(C═O)NR^(34a)R^(34b), —NHSO₂NR^(34a)R^(34b), —NH(C═O)NR^(34a)R^(34b),and —N═NR³⁵; wherein R³³, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(34a) and R^(34b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁵, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl; and wherein Ar³ is selected from aryl and heteroaryl and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy),C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO₂R³⁶, —CO₂R³⁶, —(C1-C4alkyl)CO₂R³⁶, —(C2-C4 alkenyl)CO₂R³⁶, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4alkyl), —SO₂(C1-C4 alkyl), —(C═O)NR^(37a)R^(37b), —SO₂NR^(37a)R^(37b),—O(C═O)NR^(37a)R^(37b), —NHSO₂NR^(37a)R^(37b), —NH(C═O)NR^(37a)R^(37b),and —N═NR³⁸; wherein R³⁶, when present, is selected from hydrogen, C1-C8alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by aformula:

wherein each of R^(37a) and R^(37b), when present, is independentlyselected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;wherein R³⁸, when present, is selected from hydrogen, C1-C4 alkyl, andphenyl.
 11. The method of claim 9, wherein the compound is:


12. The method of claim 9, wherein the activating agent is triflicanhydride.
 13. The method of claim 9, wherein the base is pyridine.